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circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/SHOC2 feedback loop
Wenqing Xua, Zhihong Zhongb, Long Gub, Yiming Xiaob, BinShen Chenc, Weilie Hua,
Corresponding author
hwlwei@hotmail.com

Corresponding author.
a Department of Urology, The First School of Clinical Medicine of Southern Medical University, Guangzhou City, Guangdong Province, China
b Department of Urology, Guangzhou Development District Hospital, Guangzhou City, Guangdong Province, China
c Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou City, Guangdong Province, China
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">miR-491-5p is absorbed by circCPA4&#46;</span> &#40;A&#41; circCPA4 and miR-491-5p had potential binding sites&#46; &#40;B&#8210;C&#41; Lower miR-491-5p expression in PC tissues versus normal tissues and in PC cell lines versus RWPE&#46; &#40;D&#8210;E&#41; circCPA4 and miR-491-5p had a targeting binding relationship&#46; &#40;F&#41; circCPA4 and miR-491-5p were localized in the cytoplasm of PC3 cells&#46; &#40;G&#41; circCPA4 knockdown elevated miR-491-5p expression&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0008" class="elsevierStylePara elsevierViewall">Prostate Cancer &#40;PC&#41; is a common cancer type affecting men&#39;s health worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> PC originates from the gland epithelial cells of the prostate and is characterized by the uncontrolled growth and proliferation of cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Currently&#44; treatment options for PC include surgery&#44; immunotherapy&#44; hormone therapy&#44; radiation therapy&#44; and chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> Despite advances in PC treatment&#44; mortality and morbidity associated with the disease remain high&#44; and new treatment strategies are urgently needed&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">Upon reverse splicing&#44; circRNAs are formed by covalently linking their downstream 3&#8242;end and upstream 5&#8242;end&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> circRNAs are expressed in large quantities in tissues and involve gene regulation&#44; including transcription and post-transcriptional regulation&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> Dysregulation of circRNAs in cancers&#44; including PC&#44; has been shown&#44; indicating their potential as a diagnostic and therapeutic target&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> circCPA4 has been elucidated to be abundant in cancers and involved in the biological activities of cancer cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0009"><span class="elsevierStyleSup">9-11</span></a> However&#44; its biological function in PC remains unclear&#46; miRNAs are crucial in gene expression modification<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> and miRNAs can target specific mRNAs and regulate their expression&#44; while circRNAs can act as a sponge for miRNAs and regulate their availability to targeted mRNAs&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> This means that miRNA and circRNA can interact with each other to form complex regulatory networks and participate in the regulation of various activities of PC&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> However&#44; whether circCPA4 regulates miRNA&#47;mRNA networks and is involved in PC development remains unclear&#46;</p><p id="para0011" class="elsevierStylePara elsevierViewall">This study investigated the biological function of circCPA4 in PC and put forward a hypothesis that circCPA4 participates in the development process of PC by regulating downstream miRNA&#47;mRNA networks&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Clinical samples</span><p id="para0012" class="elsevierStylePara elsevierViewall">This study obtained approval by the Ethics Committee of The First School of Clinical Medicine of Southern Medical University&#46; All patients presented informed consent&#46; Thirty-nine pairs of PC tissue samples and normal tissue samples were obtained from The First School of Clinical Medicine of Southern Medical University and confirmed by the pathologist&#46; Patients with preoperative pathological diagnosis of PC signed informed consent before being enrolled in the study&#46; Patients were excluded if they had a second primary tumor&#44; HIV or syphilis virus&#44; severe liver&#44; kidney or other systemic disease&#44; or other malignant disease&#44; and had received chemotherapy or radiation before surgery&#46; After excision or biopsy&#44; the tissue was rapidly frozen and stored at -80&#176;C&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">RT-qPCR</span><p id="para0013" class="elsevierStylePara elsevierViewall">A NanoDrop 2000 spectrophotometer &#40;Thermo Fisher Scientific&#41; measured the quality of RNA obtained from cells&#47;tissues using a Trizol reagent &#40;Life Technologies&#41;&#46; PrimeScript RT Master Mix &#40;RR036A&#59; Takara&#41; was employed to generate cDNA of circRNA and mRNA&#44; whereas PrimeScript&#8482;RT Reagent Kit &#40;RR037A&#59; Takara&#41; was purchased for miRNA reverse transcription&#46; ChamQ SYBR qPCR Master Mix &#40;Q311-02&#59; Vazyme&#41; and Roter Gene 3000 sequence detection system &#40;Corbett Research&#44; Australia&#41; performed PCR&#46; To calculate relative gene expression&#44; 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method was utilized&#44; and GAPDH or U6 was considered endogenous control&#46; The primer sequence is found in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Cell culture</span><p id="para0014" class="elsevierStylePara elsevierViewall">PC cell lines &#40;PC3&#44; DU145&#44; VCaP&#44; and 22RV1&#41; and normal prostate cell lines &#40;RWPE&#41; were derived from ATCC&#46; For the 4 PC cell lines&#44; the cell culture was RPMI-1640 &#40;Gibco&#41; plus 10&#160;&#37; FBS &#40;Gibco&#41;&#44; 100 U&#47;mL penicillin and 100&#160;&#956;g&#47;mL streptomycin &#40;Invitrogen&#41;&#46; Keratinocyte serum-free medium &#40;Gibco&#41; was adopted to culture RWPE cells&#46; A humidified atmosphere was needed for cell culture at 37&#176;C and 5&#160;&#37; CO<span class="elsevierStyleInf">2</span>&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Actinomycin D treatment</span><p id="para0015" class="elsevierStylePara elsevierViewall">PC3 cells were plated in 6-well plates &#40;5&#215;10<span class="elsevierStyleSup">5</span> cells&#47;well&#41; and allowed to 2h culture&#46; RNA stability was analyzed by PCR after actinomycin D was administered &#40;2&#160;&#956;g&#47;mL&#44; Sigma&#41; at a specific time point&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">RNAse R treatment</span><p id="para0016" class="elsevierStylePara elsevierViewall">10&#160;&#956;g RNA from PC3 cells was mixed with RNAse R &#40;3 U&#47;g&#44; Epicenter&#41; at 37&#176;C and after 30&#160;min&#44; circRNA and linear RNA were evaluated using PCR&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">FISH assay</span><p id="para0017" class="elsevierStylePara elsevierViewall">RiboBio &#40;Guangzhou&#44; China&#41; provided Cy3-labeled circCPA4 and DIG-labeled lock-in nucleic acid miR-491-5p probes&#44; as well as a FISH kit to obtain images&#46; A1Si laser scanning confocal microscope &#40;Nikon&#41; and ModFit LT software were auxiliary for data analysis&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Cell transfection</span><p id="para0018" class="elsevierStylePara elsevierViewall">Lipofectamine 3000 &#40;Invitrogen&#41; transfected circCPA4 and SHOC2 targeted siRNA and pcDNA 3&#46;1 overexpression vectors as well as miR-491-5p mimic or miR-491-5p inhibitor into PC3 cells&#46; All vectors were provided by RiboBio&#46; RT-qPCR performed after 48 transfections verified the transfection efficiency&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Colony formation test</span><p id="para0019" class="elsevierStylePara elsevierViewall">Six-well plates were covered with RPMI-1640 containing 10&#160;&#37; FBS&#44; in which cells were seeded at 2000 cells&#47;well for 10d&#46; After fixation and crystal violet staining&#44; the colonies were imaged and counted&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">EdU experiment</span><p id="para0020" class="elsevierStylePara elsevierViewall">EdU experiment was conducted using the cell-light EdU Apollo 488 In Vitro kit &#40;C10310-3&#59; RiboBio&#41;&#46; In brief&#44; cells were fixed with 4&#160;&#37; paraformaldehyde &#40;P0099&#59; Beyotime&#41; and permeated with 0&#46;5&#160;&#37; Triton X-100 after EdU staining &#40;50 nM&#41; and stained with 1&#215;Apollo&#174; fluorescent dye&#46; The nuclei were restained with DAPI&#46; EdU-positive cells were photographed using FSX100 microscope &#40;Olympus&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Flow cytometry</span><p id="para0021" class="elsevierStylePara elsevierViewall">PC3 cells were assayed by Annexin V-FITC apoptosis detection kit &#40;Vazyme&#41;&#46; Cells after rinsing with cold PBS &#40;Sangon&#44; China&#41; were resuspended in a binding buffer and reacted darkly with 5&#160;&#181;L Annexin V-FITC and 5&#160;&#181;L PI for 15&#160;min&#46; Analyses of flow cytometry &#40;Beckman Coulter&#44; USA&#41; were conducted to determine apoptosis rates&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Transwell tests</span><p id="para0022" class="elsevierStylePara elsevierViewall">The Transwell chamber &#40;Corning&#44; USA&#41; was equipped with an 8&#160;&#956;m pore size polycarbonate filter&#46; Cells &#40;5&#215;10<span class="elsevierStyleSup">4</span>&#41; in serum-free medium were coated on the upper cavity&#44; in which Matrigel &#40;BD356230&#44; Corning&#41; was only required for invasion assay&#46; Meanwhile&#44; 600&#160;&#956;L 10&#160;&#37; FBS was fulfilled with the lower cavity&#46; After culture&#44; cells transferred to the lower cavity were fixed in 95&#160;&#37; ethanol for 15&#160;min&#44; stained with 0&#46;1&#160;&#37; crystal violet for 20&#160;min&#44; and counted under a microscope &#40;Leica Microsystems&#41; in 5 regions&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Immunoblot</span><p id="para0023" class="elsevierStylePara elsevierViewall">Proteins were isolated from tissues and cells using RIPA lysis buffer &#40;Thermo Fisher&#41; and quantified using a BCA analysis kit &#40;BioVision&#44; USA&#41;&#46; The proteins were separated on a 10&#160;&#37; SDS-polyacrylamide gel and transferred to a PVDF membrane &#40;Thermo Fisher&#41; which was covered with 5&#160;&#37; milk and incubated with the primary antibody overnight and the secondary antibody conjugated with horseradish peroxidase &#40;BD Biosciences&#41; for 1h&#46; Protein bands were evaluated using the SynGene system and GeneSnap software &#40;SynGene&#44; USA&#41;&#46; Primary antibodies&#58; N-cadherin &#40;13116&#44; Cell Signaling Technology&#41;&#44; GAPDH &#40;2118&#44; Cell Signaling Technology&#41;&#44; E-cadherin &#40;3195&#44; Cell Signaling Technology&#41;&#44; cleaved caspase-3 &#40;9664&#44; Cell Signaling Technology&#41;&#44; Ki-67 &#40;ab16667&#44; Abcam&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Dual luciferase reporter experiment</span><p id="para0024" class="elsevierStylePara elsevierViewall">circCPA4 and SHOC2 Wild Type &#40;WT&#41; sequences containing predicted miR-491-5p binding sites were cloned and inserted into firefly luciferase PCL-3 vectors &#40;E1751&#44; Promega&#44; USA&#41;&#44; named circCPA4-WT and SHOC2-WT&#46; circCPA4 and SHOC2 Mutants &#40;MUTs&#41; were inserted into luciferase vectors and named circCPA4-MUT and SHOC2-MUT&#46; For co-transfection of luciferase reporter and miR-491-5p mimic and mimic NC&#44; Lipofectamine 3000 was utilized&#46; Luciferase Reporter Assay System &#40;E1960&#44; Promega&#41; analyzed luciferase activity at 48h&#46;</p></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">RIP experiment</span><p id="para0025" class="elsevierStylePara elsevierViewall">RIP assay was performed using the Magna RIP kit &#40;Millipore&#41;&#46; Cells were lysed in 100&#160;&#956;L RIP lysis buffer containing a mixture of RNAse inhibitors &#40;Promega&#41; and protease inhibitors &#40;Roche&#41;&#46; After DNase I &#40;Roche&#41; treatment&#44; 900&#160;&#956;L RIP immunoprecipitation buffer was added to the lysate and reacted with antibody-conjugated magnetic beads &#40;anti-AgO2 or anti-IgG&#41;&#46; The beads after RIP washing buffer treatment were processed with protease K for 30&#160;min before PCR analysis&#46;</p></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">Tumor growth in vivo</span><p id="para0026" class="elsevierStylePara elsevierViewall">All experimental mouse procedures were approved by the Animal Ethics Committee of The First School of Clinical Medicine of Southern Medical University&#44; and the researchers minimized the suffering of the mice&#46; Six eight-week-old male BALB&#47;c nude mice were purchased from Hunan SJA Animal Experimental Co&#46;&#44; Ltd&#46; As for <span class="elsevierStyleItalic">in vivo</span> tumor metastasis studies&#44; PC3 cells &#40;5&#215;10<span class="elsevierStyleSup">6</span> cells&#41; with stable circCPA4 knockdown or non-knockdown circCPA4 were inoculated subcutaneously into mouse armpits&#46; During the following 30d&#44; using a digital caliper&#44; the size of tumors was measured periodically in the mice&#46; Tumor volume &#40;cm<span class="elsevierStyleSup">3</span>&#41;&#160;&#61;&#160;0&#46;5&#160;&#215;&#160;length&#160;&#215;&#160;width<span class="elsevierStyleSup">2</span>&#46; After that&#44; the excised tumor was weighed&#44; fixed with 4&#160;&#37; paraformaldehyde&#44; and paraffin-embedded for IHC staining&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">Data analysis</span><p id="para0027" class="elsevierStylePara elsevierViewall">GraphPad Prism 9&#46;0 was utilized for data analysis&#46; Data were presented as mean &#177; standard deviation&#46; Two-tailed Student <span class="elsevierStyleItalic">t</span>-test and one-way ANOVA compared the data&#46; Chi-Square assay assessed the association of circCPA4 with clinicopathologic features in PC patients&#59; &#42;p &#60; 0&#46;05 was statistically significant&#46;</p></span></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">circCPA4 high expression in PC</span><p id="para0028" class="elsevierStylePara elsevierViewall">circCPA4 expression pattern in PC was examined&#46; PC tissues &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>A&#41; as well as four PC cell lines &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>B&#41; had higher circCPA4 levels than controls&#46; To examine the ring structure of circCPA4&#44; both actinomycin D and RNAse R treatments were conducted&#44; indicating that the two methods caused no change in the RNA stability of circCPA4&#44; but reduced that of linear RNA &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a> C and D&#41;&#46; Also&#44; circCPA4 could be amplified by outward-diverging primers in cDNA&#44; but circCPA4 could not be amplified from gDNA &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>E&#41;&#46; Abnormal expression of circCPA4 was highly correlated with TNM staging and distal metastasis in PC patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#41;&#46; A poorer survival prognosis was observed for those with high circCPA4 expression &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>F&#41;&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><elsevierMultimedia ident="tbl0002"></elsevierMultimedia></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">circCPA4 deficiency inhibits PC3 cell metastasis</span><p id="para0029" class="elsevierStylePara elsevierViewall">circCPA4-targeted siRNA was transfected into PC3 cells to analyze the biological function of circCPA4&#46; Transfection of si-circCPA4 reduced circCPA4 expression effectively &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#41;&#46; Colony formation and EdU tests noted that circCPA4 knockdown reduced cell proliferation capacity and EdU-positive rate &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a> B and C&#41;&#46; Also&#44; circCPA4 depletion inhibited protein expression of proliferating protein Ki-67 &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>F&#41;&#46; Cellular apoptosis was evaluated&#44; as manifested by increased apoptosis&#44; and cleaved caspase-3 protein expression in circCPA4-knockdown cells &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a> D and F&#41;&#46; Transwell assay presented that circCPA4 depletion reduced the number of invading and migrating cells &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>E&#41; and suppressed N-cadherin and increased E-cadherin expressions &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>F&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">circCPA4 competitively decoys miR-491-5p</span><p id="para0030" class="elsevierStylePara elsevierViewall">The study predicted from the bioinformatics website that potential binding sites for circCPA4 and miR-491-5p existed &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>A&#41;&#46; miR-491-5p in PC was evaluated by RT-qPCR&#44; showing low expression in PC tissues and four PC cell lines &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a> B and C&#41;&#46; Therefore&#44; circCPA4 might be targeted to miR-491-5p&#44; which was verified by dual luciferase reporter assay and RIP assay&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>D&#44; E&#44; WT-circCPA4 in combination with miR-491-5p mimic could reduce luciferase activity&#44; and there was a high level of enrichment in Ago2 beads for circCPA4 and miR-491-5p&#46; FISH experiments further confirmed that circCPA4 and miR-491-5p were colocalized in the cytoplasm of PC3 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>F&#41;&#46; miR-491-5p levels in PC3 cells were restored after circCPA4 knockdown &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>G&#41;&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">circCPA4 interacts with miR-491-5p in affecting the biological behavior of PC3 cells</span><p id="para0031" class="elsevierStylePara elsevierViewall">PC3 cells were co-transfected with pcDNA 3&#46;1-circCPA4 and miR-491-5p mimic&#46; RT-qPCR detected that pcDNA 3&#46;1-circCPA4 promoted circCPA4 and inhibited miR-491-5p levels&#44; while miR-491-5p mimic restored miR-491-5p levels &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>A&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4B</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0004">4</a>C&#44; and <a class="elsevierStyleCrossRef" href="#fig0004">4</a>F showed that pcDNA 3&#46;1-circCPA4 increased cell proliferation and EdU positive rate&#44; and promoted Ki-67 expression&#44; but this phenomenon was blocked by miR-491-5p mimic&#46; At the same time&#44; pcDNA 3&#46;1-circCPA4 reduced cell apoptosis rate and inhibited cleaved caspase-3 expression&#44; but this action was impaired by miR-491-5p mimic &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a> D and F&#41;&#46; Transwell tests indicated that pcDNA 3&#46;1-circCPA4 promoted cell invasion and migration ability&#44; but miR-491-5p mimic destroyed this phenomenon &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>E&#41;&#46; Immunoblot suggested that pcDNA 3&#46;1-circCPA4 enhanced N-cadherin and lowered E-cadherin protein expression&#44; but miR-491-5p mimic blocked the changes of these proteins &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>F&#41;&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0024" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">miR-491-5p and SHOC2 are interacted</span><p id="para0032" class="elsevierStylePara elsevierViewall">Potential binding sites of miR-491-5p and SHOC2 were predicted through bioinformatics websites &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5A</a>&#41;&#46; SHOC2 expression was then evaluated by immunoblot&#44; presenting a higher level in both PC tissues and cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a> B and C&#41;&#46; Dual luciferase reporter experiments addressed that co-transfection with WT-SHOC2 and miR-491-5p mimic reduced luciferase activity &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5D</a>&#41;&#46; RIP experiments observed the enrichment of SHOC2 and miR-491-5p in Ago2 magnetic beads &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5E</a>&#41;&#46; Increasing or decreasing miR-491-5p inhibited and promoted SHOC2 expression in PC3 cells&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5F</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0032">circCPA4 mediates and affects the biological behavior of PC3</span><p id="para0033" class="elsevierStylePara elsevierViewall">PC3 cells were co-transfected with pcDNA 3&#46;1-circCPA4 and si-SHOC2&#46; pcDNA 3&#46;1-circCPA4 elevated SHOC2 protein expression&#44; but this effect was suppressed partially by si-SHOC2 &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>A&#41;&#46; pcDNA 3&#46;1-circCPA4 increased cell proliferation&#44; EdU-positive rate&#44; and Ki-67 protein expression&#44; but si-SHOC2 obstructed this phenomenon &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a> B&#44; C&#44; F&#41;&#46; Additionally&#44; pcDNA 3&#46;1-circCPA4 reduced apoptosis and cleaved caspase-3 protein levels&#44; while si-SHOC2 prevented this &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a> D and F&#41;&#46; Transwell manifested that pcDNA 3&#46;1-circCPA4 increased the number of invasive and migratory cells&#44; while si-SHOC2 blocked this effect &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>E&#41;&#46; Immunoblot determined that pcDNA 3&#46;1-circCPA4 promoted N-cadherin expression and decreased E-cadherin expression&#44; while si-SHOC2 prevented alternations in these proteins &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>F&#41;&#46;</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span><span id="sec0026" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0033">circCPA4 knockdown inhibits PC tumor growth</span><p id="para0034" class="elsevierStylePara elsevierViewall">Tumor growth was observed after circCPA4 interference in mice&#46; Knocking down circCPA4 lowered tumor volume and weight &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7</a> A&#8210;C&#41;&#46; IHC staining suggested that circCPA4 deficiency reduced SHOC2 and Ki-67 expressions in tumors &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7D</a>&#41;&#46;</p><elsevierMultimedia ident="fig0007"></elsevierMultimedia></span></span><span id="sec0027" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0034">Discussion</span><p id="para0035" class="elsevierStylePara elsevierViewall">Abnormal expression of circRNA affects PC development&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> This study highlights that downregulating circCPA4 inhibited the metastasis of PC&#46; The identification of miR-491-5p&#47;SHOC2 axis as a downstream target of circCPA4 provides a potential pathway for developing targeted therapeutics for PC&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">In fact&#44; circCPA4 has been emphasized to correlate with TNM staging&#44; lymph node metastasis&#44; and tumor size in lung cancer patients&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> The study further confirmed that abnormally high expression of circCPA4 was associated with TNM staging and distal metastasis in PC patients&#46; In addition&#44; circCPA4 expression levels had prognostic values for overall survival in PC patients&#46; This highlights the potential clinical role of circCPA4 as a diagnostic and prognostic biomarker for PC&#46; Thus&#44; a deeper understanding of the molecular mechanisms of circCPA4&#8242;s role in PC could provide new insights into disease pathogenesis&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">This study declared that circCPA4 was involved in regulating the proliferation&#44; invasion&#44; and migration&#44; apoptosis&#44; and EMT processes of PC3 cells&#46; EMT is a key process of cancer invasion and metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> Since high circCPA4 is highly associated with remote metastasis in PC patients&#44; it is suggested that circCPA4&#8242;s promotion of invasive migration and EMT processes will contribute to remote metastasis of PC&#46; In addition&#44; it has been declared that high expression of circCPA4 can block apoptosis and induce proliferation of cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> showing consistency with the results of this study&#46;</p><p id="para0038" class="elsevierStylePara elsevierViewall">Notably&#44; this study further confirmed the ring structure of circCPA4 in PC3 cells&#46; Compared with linear RNA&#44; circRNA is more stable&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> Therefore&#44; circCPA4 has a more permanent role in regulating downstream miRNA expression and function&#44; which will continue to influence the malignant development of PC&#46; circCAP4 regulates the biological behavior of different cancers through miRNA&#47;mRNA networks&#46; These miRNA&#47;mRNA networks include miR-214-3p&#47;TGIF2<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> and miR-760&#47;MEF2D&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> This study identified a novel mechanism network for circCPA4 in PC&#46; circCPA4 promoted SHOC2 expression through competitive adsorption of miR-491-5p&#44; thus accelerating multiple biological behaviors of PC3 cells&#46;</p><p id="para0039" class="elsevierStylePara elsevierViewall">However&#44; understanding of the molecular mechanism and biological function of circCPA4 is still limited&#44; and further studies are needed&#46; Secondly&#44; circRNA and miRNA&#47;mRNA targeting regulatory network is extremely complex&#44; which needs to be improved in subsequent studies&#46; In addition&#44; how to detect circCPA4 quickly&#44; effectively&#44; and accurately in the clinic is also a problem that needs to be solved&#46;</p><p id="para0040" class="elsevierStylePara elsevierViewall">Together&#44; the circCPA4&#47;mi-491-5p&#47;SHOC2 axis is involved in PC by regulating cell proliferation&#44; invasion and migration&#44; apoptosis&#44; and EMT&#46; Thus&#44; circCPA4 may be a promising target for developing novel diagnostic and therapeutic strategies for PC&#46;</p></span><span id="sec0028" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0035">Data available</span><p id="para0041" class="elsevierStylePara elsevierViewall">Data is available from the corresponding author on request&#46;</p></span><span id="sec0029" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0036">Ethical approval</span><p id="para0042" class="elsevierStylePara elsevierViewall">All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and&#47;or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards&#46; All subjects were approved by The First School of Clinical Medicine of Southern Medical University&#46;</p><p id="para0043" class="elsevierStylePara elsevierViewall">This study followed the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health&#46; The animal experiments were approved by the ethics committee of The First School of Clinical Medicine of Southern Medical University&#46;</p></span></span>"
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          "titulo" => "Materials and methods"
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              "titulo" => "Cell culture"
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              "titulo" => "Actinomycin D treatment"
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              "titulo" => "RNAse R treatment"
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              "titulo" => "FISH assay"
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              "titulo" => "Cell transfection"
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              "titulo" => "Colony formation test"
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              "titulo" => "EdU experiment"
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              "titulo" => "Immunoblot"
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              "titulo" => "circCPA4 high expression in PC"
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              "titulo" => "circCPA4 deficiency inhibits PC3 cell metastasis"
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              "titulo" => "circCPA4 competitively decoys miR-491-5p"
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              "titulo" => "miR-491-5p and SHOC2 are interacted"
            ]
            5 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "circCPA4 mediates and affects the biological behavior of PC3"
            ]
            6 => array:2 [
              "identificador" => "sec0026"
              "titulo" => "circCPA4 knockdown inhibits PC tumor growth"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0027"
          "titulo" => "Discussion"
        ]
        7 => array:2 [
          "identificador" => "sec0028"
          "titulo" => "Data available"
        ]
        8 => array:2 [
          "identificador" => "sec0029"
          "titulo" => "Ethical approval"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-10-19"
    "fechaAceptado" => "2023-11-19"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1903267"
          "palabras" => array:5 [
            0 => "circCPA4"
            1 => "Prostate cancer"
            2 => "miR-491-5p"
            3 => "SHOC2"
            4 => "Invasion"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara010" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">circCPA4 deficiency inhibits PC3 cell metastasis&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">circCPA4 interacts with miR-491-5p in affecting the biological behavior of PC3 cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">circCPA4 mediates and affects the biological behavior of PC3&#46;</p></li></ul></p></span>"
    ]
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objective</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">circCPA4 has been defined to be an oncogenic gene&#46; This study examined whether circCPA4 regulates Prostate Cancer &#40;PC&#41; development and revealed its molecular mechanism&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">PC tissues and PC cell lines were collected&#44; in which circCPA4&#47;miR-491-5p&#47;SHOC2 levels were evaluated by RT-qPCR and immunoblot&#46; Colony formation assay and EdU assay assessed cell proliferation&#44; flow cytometry measured apoptosis&#44; and Transwell assessed invasion and migration&#46; Ki-67&#44; cleaved caspase-3&#44; E-cadherin&#44; and N-cadherin were evaluated by immunoblot&#46; Based on the luciferase reporter assay and RIP assay the authors investigated the targeting relationship between circCPA4&#47;miR-491-5p&#47;SHOC2&#46; The effect of circCPA4 on tumor growth was evaluated by xenotransplantation in nude mice&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">circCPA4 and SHOC2 levels were abundant while miR-491-5p expression was low in PC&#46; Loss of circCPA4 decreased the proliferation and EdU-positive rate of PC cells&#44; enhanced apoptosis&#44; and inhibited invasion&#44; migration&#44; and EMT&#46; Upregulation of circCPA4 forced the malignant behaviors of PC cells&#44; and this promotion could be abolished when miR-491-5p was overexpressed or SHOC2 was silenced&#46; CircCAP4 competitively decoyed miR-491-5p mediating SHOC2 expression&#46; circCAP4 suppression inhibited PC tumor growth&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara014" class="elsevierStyleSimplePara elsevierViewall">circCAP4 acts as a novel oncogenic factor in PC&#44; accelerating the malignant behavior of PC cells via miR-491-5p&#47;SHOC2 interaction&#46; This novel ceRNA axis may be a potential target for PC drug development and targeted therapy in the future&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abss0002"
            "titulo" => "Objective"
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            "identificador" => "abss0003"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abss0004"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abss0005"
            "titulo" => "Conclusion"
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      0 => array:8 [
        "identificador" => "fig0001"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">circCPA4 high expression in PC&#46;</span> &#40;A&#8210;B&#41; Higher circCPA4 expression in PC tissues versus normal tissues and in PC cell lines versus RWPE&#46; &#40;C&#8210;D&#41; circCPA4 had ring structure and high stability&#46; &#40;E&#41; Negative relationship between circCPA4 and survival prognosis of PC patients&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0002"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 2372
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            "Tamanyo" => 741038
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          0 => array:3 [
            "identificador" => "alt0002"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">circCPA4 knockdown suppresses PC3 cell activities&#46;</span> &#40;A&#41; si-circCPA4 lowered circCPA4 expression&#46; &#40;B&#8210;C&#41; circCPA4 reduced cell proliferation&#46; &#40;D&#41; circCPA4 enhanced apoptosis rate&#46; &#40;E&#41; circCPA4 reduced invasion and migration abilities&#46; &#40;F&#41; circCPA4 reduced Ki-67 and N-cadherin and elevated cleaved caspase-3 and E-cadherin&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "fig0003"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
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          0 => array:3 [
            "identificador" => "alt0003"
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        "descripcion" => array:1 [
          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">miR-491-5p is absorbed by circCPA4&#46;</span> &#40;A&#41; circCPA4 and miR-491-5p had potential binding sites&#46; &#40;B&#8210;C&#41; Lower miR-491-5p expression in PC tissues versus normal tissues and in PC cell lines versus RWPE&#46; &#40;D&#8210;E&#41; circCPA4 and miR-491-5p had a targeting binding relationship&#46; &#40;F&#41; circCPA4 and miR-491-5p were localized in the cytoplasm of PC3 cells&#46; &#40;G&#41; circCPA4 knockdown elevated miR-491-5p expression&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "fig0004"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1941
            "Ancho" => 3500
            "Tamanyo" => 784249
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0004"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">circCPA4 interacts with miR-491-5p and affects the biological behavior of PC3 cells&#46;</span> Based on pcDNA 3&#46;1-circCPA4&#44; miR-491-5p mimic was further treated&#46; &#40;A&#41; miR-491-5p mimic restored miR-491-5p expression&#46; &#40;B&#8210;C&#41; miR-491-5p mimic suppressed cell proliferation&#46; &#40;D&#41; miR-491-5p mimic activated apoptosis rate&#46; &#40;E&#41; miR-491-5p mimic suppressed invasion and migration abilities&#46; &#40;F&#41; miR-491-5p mimic suppressed Ki-67 and N-cadherin and enhanced cleaved caspase-3 and E-cadherin&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 2742
            "Ancho" => 3167
            "Tamanyo" => 478411
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        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0005"
            "detalle" => "Fig&#46; "
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        "descripcion" => array:1 [
          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">SHOC2 shows the downstream target gene of miR-491-5p&#46;</span> &#40;A&#41; SHOC2 and miR-491-5p shared potential binding sites&#46; &#40;B&#8210;C&#41; Higher SHOC2 expression in PC tissues versus normal tissues and in PC cell lines versus RWPE&#46; &#40;D&#8210;E&#41; SHOC2 and miR-491-5p had a targeting binding relationship&#46; &#40;F&#41; miR-491-5p mediated SHOC2 protein expression&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "fig0006"
        "etiqueta" => "Fig&#46; 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 1832
            "Ancho" => 3500
            "Tamanyo" => 735979
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0006"
            "detalle" => "Fig&#46; "
            "rol" => "short"
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        "descripcion" => array:1 [
          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">circCPA4 and SHOC2 affect the biological behavior of PC3 cells&#46;</span> Based on pcDNA 3&#46;1-circCPA4&#44; si-SHOC2 was further processed&#46; &#40;A&#41; si-SHOC2 lowered SHOC2 expression&#46; &#40;B&#8210;C&#41; si-SHOC2 limited cell proliferation&#46; &#40;D&#41; si-SHOC2 induced apoptosis rate&#46; &#40;E&#41; si-SHOC2 hampered invasion and migration abilities&#46; &#40;F&#41; si-SHOC2 limited Ki-67 and N-cadherin and induced cleaved caspase-3 and E-cadherin&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "fig0007"
        "etiqueta" => "Fig&#46; 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 2183
            "Ancho" => 3167
            "Tamanyo" => 947827
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0007"
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        "descripcion" => array:1 [
          "en" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Inhibition of PC tumor growth by knocking down circCPA4&#46;</span> &#40;A&#41; Representative pictures of tumors&#46; &#40;B&#41; tumor volume&#46; &#40;C&#41; tumor weight&#46; &#40;D&#41; SHOC2 and Ki-67 expression in tumors &#40;IHC staining&#41;&#46; Data were expressed as mean &#177; SD&#46; &#42;p &#60; 0&#46;05&#46; For Figure 1&#8210;6&#44; n&#160;&#61;&#160;3&#59; for <a class="elsevierStyleCrossRef" href="#fig0007">Figure 7</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0007">n</a>&#160;&#61;&#160;5&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0001"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "detalle" => "Table "
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        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Primer sequences &#40;5&#8242; - 3&#8242;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0003"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="top"><span class="elsevierStyleBold">circCPA4</span></td><a name="en0004"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">Forward&#58; 5&#8242;- TCAAACTCAAGCCCTTTTAGACA-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0006"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reserse&#58; 5&#8242;- TCAGGAAAGTCTGCGGCAAT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="top"><span class="elsevierStyleBold">miR-491-5p</span></td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Forward&#58; 5&#8242;-GAGTGGGGAACCCTTCC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reserse&#58; 5&#8242;- TGGTGTCGTGGAGTCG-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0011"></a><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="top"><span class="elsevierStyleBold">SHOC2</span></td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Forward&#58; 5&#8242;- CCAGCAGAGGTGGGATGTTT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reserse&#58; 5&#8242;- GTGCTGCAAGTCAAGGTTGG-3&#8242;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Forward&#58; 5&#8242;- CACCCACTCCTCCACCTTTG-3&#8242;<span class="elsevierStyleHsp" style=""></span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reserse&#58; 5&#8242;- CCACCACCCTGTTGCTGTAG-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              ]
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "alt0009"
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                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top" scope="col"><span class="elsevierStyleBold">Characteristic</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top" scope="col"><span class="elsevierStyleBold">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><a name="en0032a"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0028"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">n&#160;&#61;&#160;39</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0029"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Low &#40;n&#160;&#61;&#160;20&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0030"></a><th class="td" title="\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">High &#40;n&#160;&#61;&#160;19&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0032c"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Age &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top">0&#46;3333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;&#8805; 60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032d"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;&#60; 60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032e"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Tumor size &#40;cm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top">0&#46;4075&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0052"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;&#8805; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032f"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;&#60; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032h"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Lymph node metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top">0&#46;2651&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0067"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0070"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032i"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0072"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0073"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032ka"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0077"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">TNM stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0081"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top">0&#46;0015&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0082"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;I&#8210;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0085"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032kaa"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0087"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;II&#8210;IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0089"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0090"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032kadf"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0092"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Distal transfer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0093"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0096"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " align="left" valign="top">0&#46;0008&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0097"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0100"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032kamkj"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0102"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0103"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0104"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0105"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032kakuij"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spara009" class="elsevierStyleSimplePara elsevierViewall">Correlation analysis of clinicopathological characteristics of patients with circCPA4 and PC&#46;</p>"
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec1"
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            0 => array:3 [
              "identificador" => "bib0001"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Future directions for precision oncology in prostate cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K Mizuno"
                            1 => "H&#46; Beltran"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pros.24354"
                      "Revista" => array:7 [
                        "tituloSerie" => "Prostate"
                        "fecha" => "2022"
                        "volumen" => "82"
                        "numero" => "Suppl 1"
                        "paginaInicial" => "S86"
                        "paginaFinal" => "S96"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35657153"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0002"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "French ccAFU guidelines - update 2020&#8210;2022&#58; prostate cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F Rozet"
                            1 => "P Mongiat-Artus"
                            2 => "C Hennequin"
                            3 => "JB Beauval"
                            4 => "P Beuzeboc"
                            5 => "L Cormier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1166-7087(20)30752-1"
                      "Revista" => array:7 [
                        "tituloSerie" => "Prog Urol"
                        "fecha" => "2020"
                        "volumen" => "30"
                        "numero" => "12S"
                        "paginaInicial" => "S136"
                        "paginaFinal" => "S251"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33349424"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0003"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metastatic prostate cancer&#58; treatment options"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "V Achard"
                            1 => "PM Putora"
                            2 => "A Omlin"
                            3 => "T Zilli"
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Article information
ISSN: 18075932
Original language: English
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