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ORIGINAL ARTICLE
RNA-binding protein with serine-rich domain 1 regulates microsatellite instability of uterine corpus endometrial adenocarcinoma
Xiaojuan Liu, Hui Ma, Lisha Ma, Kun Li, Yanhua Kang
Corresponding author
yanhkang@126.com

Corresponding author.
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Hebei North University, Qiaoxi District, Zhangjiakou City 075000, Hebei Province, P.R. China
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; <span class="elsevierStyleItalic">RNPS1</span> expression&#44; &#40;B&#41; quantitation of the <span class="elsevierStyleItalic">RNPS1</span> expression levels from the western blots&#44; and &#40;C&#41; IHC staining analysis for <span class="elsevierStyleItalic">RNPS1</span> in para-tumor and tumor tissues &#40;&#215;400&#41;&#46; &#40;D&#41; <span class="elsevierStyleItalic">RNPS1</span> expression in NEC&#44; KLE&#44; RL952&#44; Ishikawa&#44; and ECC-1 cells&#46; &#40;E&#41; Quantitation of the <span class="elsevierStyleItalic">RNPS1</span> expression levels in cells&#46; Protein levels were normalized to those of &#946;-actin&#46; &#40;n&#61;6&#44; &#42;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; tumor <span class="elsevierStyleItalic">vs&#46;</span> para-tumor or RL952 <span class="elsevierStyleItalic">vs&#46;</span> other cells&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Uterine corpus endometrial carcinoma &#40;UCEC&#41; is a common gynecological carcinoma with a high recurrence rate &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; Endometrioid adenocarcinoma &#40;EC&#41; is the most common pathological manifestation of UCEC&#44; with proliferative endometrial tumor cells showing glandular complexity and cellular pleomorphism &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; The risk of recurrence is intermediate or high in patients with EC after radical hysterectomy combined with pelvic and para-aortic lymphadenectomy&#44; a considerable challenge for clinics &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; Although evolving medical technologies have led to long-term declines in mortality due to EC&#44; the mechanisms and treatment of EC require further exploration&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">DNA mismatch repair &#40;MMR&#41; protein deficiency is a result of microsatellite instability &#40;MSI&#41;&#44; a hallmark of EC &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#44; providing the biological relevance and potential utility of the modal classification of EC and increasing the complexity of the genomic instability underlying tumorigenesis &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; As MMR regulation may be a prognostic factor for patients with advanced UCEC &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#44;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#44; an MMR regulator for treating UCEC needs to be identified&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">RNA-binding protein with serine-rich domain 1 &#40;<span class="elsevierStyleItalic">RNPS1</span>&#41; belongs to the mRNA nuclear export and mRNA surveillance post-splicing multiprotein complex &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41; involved in lung squamous cell and ovarian adenocarcinoma &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#44;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#46; However&#44; the mechanisms underlying the role of <span class="elsevierStyleItalic">RNPS1</span> in MMR in UCEC remain unclear&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">The Notch signaling pathway is implicated in many cancers&#44; including in the maintenance of cancer stem cells&#44; metabolism&#44; survival&#44; drug resistance&#44; epithelial-mesenchymal transition&#44; and genomic instability &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46; The Notch signaling pathway may enhance the invasive properties of EC&#44; indicating that it may serve as a promising target for the treatment of this malignancy &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">The present study aimed to determine the role of <span class="elsevierStyleItalic">RNPS1</span> in UCEC&#46; We used an <span class="elsevierStyleItalic">RNPS1</span> knockdown lentivirus &#40;sh-RNPS1&#41; to regulate MMR progression through the Notch signaling pathway and tumor progression in UCEC&#46; The present findings indicate that <span class="elsevierStyleItalic">RNPS1</span> regulates MMR in UCEC&#46; These results may provide novel strategies for UCEC therapy <span class="elsevierStyleItalic">via</span> MMR-associated mechanisms&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">UCEC specimens from patients</span><p id="para60" class="elsevierStylePara elsevierViewall">Sixteen patients pathologically diagnosed with moderately differentiated &#40;G2&#41;&#44; type I&#44; MMR-deficient EC were selected at the Department of Pathology of the First Affiliated Hospital of Hebei North University from May 2019 to May 2021&#44; with adjacent para-carcinoma tissues serving as controls&#46; All patients provided written informed consent to participate and the use of their samples was approved by the ethics committee of this study&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Bioinformatics analysis</span><p id="para70" class="elsevierStylePara elsevierViewall">The expression of <span class="elsevierStyleItalic">RNPS1</span> in various types of cancers was analyzed using TIMER2&#46;0 &#40;<a href="http://http://timer.cistrome.org/">http&#58;&#47;&#47;timer&#46;cistrome&#46;org&#47;</a>&#41;&#46; Gene set enrichment analysis &#40;GSEA&#41; data were analyzed as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; The survival of patients with UCEC showing low and high <span class="elsevierStyleItalic">RNPS1</span> expression was assayed using the Kaplan-Meier plotter &#40;<a href="http://http://kmplot.com/analysis/">http&#58;&#47;&#47;kmplot&#46;com&#47;analysis&#47;</a>&#41;&#46; Pan-cancer was analyzed as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; Genes related to mutation and prognosis were analyzed using target gene assays &#40;<a href="https://www.mutarget.com/analysis?type=target">https&#58;&#47;&#47;www&#46;mutarget&#46;com&#47;analysis&#63;type&#61;target</a>&#41;&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Cell lines and cell culture</span><p id="para80" class="elsevierStylePara elsevierViewall">Normal endometrial &#40;NECs&#59; CP-H058&#41;&#44; KLE &#40;CL-0133&#41;&#44; RL952 &#40;CL-0197&#41;&#44; and Ishikawa &#40;CL-0283&#41; cells &#40;all from Procell&#44; Wuhan&#44; China&#41; and ECC-1 cells &#40;BS-C163325&#44; BinSuiBio&#44; Shanghai&#44; China&#41; were maintained and cultured as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Animals</span><p id="para90" class="elsevierStylePara elsevierViewall">Healthy male Balb&#47;c mice &#40;Chongqing Tengxin Biotechnology Co&#46;&#44; Ltd&#46;&#44; Chongqing&#44; China&#41; were housed under specific pathogen-free conditions&#46; The mice were managed by the Care and Use of Laboratory Animals &#40;NIH Publication No&#46; 85-23&#44; revised 1996&#41;&#44; and the Ethics Committee of the First Affiliated Hospital of the Hebei North University approved the experimental design &#40;protocol No&#58; 2019ECHNU033&#41;&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Antibodies</span><p id="para100" class="elsevierStylePara elsevierViewall">The following antibodies were purchased from the respective suppliers&#58; anti-RNPS1 &#40;ab79233&#41;&#44; anti-Ki-67 &#40;ab15580&#41;&#44; anti-CEA &#40;ab207718&#41;&#44; anti-CA199 &#40;ab3982&#41;&#44; anti-CA153 &#40;ab109185&#41;&#44; anti-HE4 &#40;ab200828&#41;&#44; anti-Bcl-2 &#40;ab182858&#41;&#44; anti-Bax &#40;ab182733&#41;&#44; anti-MLH1 &#40;ab92312&#41;&#44; anti-cleaved caspase-3 &#40;ab2302&#41;&#44; anti-MSH2 &#40;ab212188&#41;&#44; anti-MSH6 &#40;ab92471&#41;&#44; and anti-PMS2 &#40;ab110638&#41; &#40;all from Abcam&#44; Cambridge&#44; USA&#41; and anti-&#946;-actin &#40;M01263-2&#59; Boster&#44; Wuhan&#44; China&#41;&#46; The secondary antibodies used were anti-rabbit IgG &#40;AS014&#41; and anti-mouse IgG &#40;H&#43;L&#41; &#40;AS003&#41;&#44; both from ABclonal &#40;Wuhan&#44; China&#41;&#44; and IMR-1A &#40;HY-100431A&#59; MedChemExpress&#44; Dallas&#44; TX&#44; USA&#41;&#46;</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">RNPS1-knockdown lentivirus administration</span><p id="para110" class="elsevierStylePara elsevierViewall">An <span class="elsevierStyleItalic">RNPS1</span>-knockdown &#40;sh-RNPS1&#41; lentivirus and a control lentivirus &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41; were designed and chemically synthesized &#40;GenePharma Corporation&#44; Shanghai&#44; China&#41; and stored at -80&#176;C&#46; The cells were transduced with the lentiviruses&#44; as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p id="para120" class="elsevierStylePara elsevierViewall">The mice were randomly assigned to the following groups &#40;n&#61;6 per group&#41;&#58; control &#40;con&#41;&#44; untreated RL952 cells&#44; or mice injected with RL952 cells&#59; sh-RNPS1&#44; RL952 cells transduced with sh-RNPS1 lentivirus or mice injected with RL952 cells infected with sh-RNPS1&#59; lentivirus control &#40;LC&#41;-shRNPS1&#44; lentivirus cells treated with <span class="elsevierStyleItalic">RNPS1</span> control lentivirus&#44; or mice injected with lentivirus cells incubated with <span class="elsevierStyleItalic">RNPS1</span> control lentivirus&#59; and IMR-1A&#43;sh-RNPS1&#44; RL952 cells incubated with sh-RNPS1 lentivirus&#44; or mice injected with RL952 cells incubated with sh-RNPS1 lentivirus or IMR-1A &#40;10 &#956;g <span class="elsevierStyleItalic">in vitro</span> or 10 mg&#47;kg <span class="elsevierStyleItalic">in vivo</span>&#41;&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">UCEC mouse model</span><p id="para130" class="elsevierStylePara elsevierViewall">The mice were subcutaneously injected with RL952 cells 5 days later&#44; as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46; The mice were sacrificed when they rapidly lost &#62;20&#37; of their weight and showed signs of deteriorating health&#44; such as hunching&#44; dehydration&#44; and labored breathing due to the metastatic burden&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">Western blotting</span><p id="para140" class="elsevierStylePara elsevierViewall">Proteins &#40;50 &#956;g&#41; from each sample were resolved by 12&#37; SDS-polyacrylamide gel electrophoresis and blotted onto nitrocellulose membranes as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41;&#46;</p></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">Immunohistochemistry &#40;IHC&#41;</span><p id="para150" class="elsevierStylePara elsevierViewall">Tissue sections &#40;4-&#956;m-thick&#41; were incubated with primary antibodies against <span class="elsevierStyleItalic">RNPS1</span> and Ki-67 at 4&#176;C overnight&#44; followed by incubation with a secondary antibody&#44; as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46;</p></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">MTT assay</span><p id="para160" class="elsevierStylePara elsevierViewall">After stirring the samples for 30 min&#44; they were passed through a filter with pores &#40;diameter&#44; 0&#46;22 &#181;m&#41;&#44; and then stored at 4&#176;C&#44; as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#41;&#46;</p></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">Statistical analysis</span><p id="para170" class="elsevierStylePara elsevierViewall">Data are expressed as the means&#177;standard deviations and were statistically analyzed by one-way or two-way ANOVA using SPSS version 19&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46; The Holm-Sidak test was used for multiple comparisons&#46; Statistical significance was set at <span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#46;</p></span></span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle190">RESULTS</span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle200">Identifying the potential function of RNPS1 in UCEC using bioinformatics analysis</span><p id="para180" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a> shows the predicted role of <span class="elsevierStyleItalic">RNPS1</span> in UCEC detected by TIMER2&#46;0&#44; GSEA&#44; and a Kaplan-Meier plotter&#46; <a class="elsevierStyleCrossRef" href="#fig1">Figure 1A</a> shows that the expression of <span class="elsevierStyleItalic">RNPS1</span>&#44; as determined by TIMER2&#46;0&#44; was higher in UCEC tumors than in normal tissues &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#41;&#46; The GSEA findings &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1B</a>&#41; showed that <span class="elsevierStyleItalic">RNPS1</span> was positively correlated with UCEC progression &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#41;&#46; Analysis of the overall survival &#40;OS&#41; and recurrence-free survival &#40;RFS&#41; indicated that the prognostic outcomes of patients with UCEC and high <span class="elsevierStyleItalic">RNPS1</span> expression &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1C and D</a>&#41; were worse &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle210">Different levels of RNPS1 in tissues or cell lines of UCEC</span><p id="para190" class="elsevierStylePara elsevierViewall">As <span class="elsevierStyleItalic">RNPS1</span> might be involved in UCEC&#44; we analyzed the differences in <span class="elsevierStyleItalic">RNPS1</span> expression among UCEC tissues or cell lines &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2</a>&#41;&#46; The <span class="elsevierStyleItalic">RNPS1</span> level was significantly higher in tumors than in para-tumor tissues &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig2">Figure 2A and B</a>&#41;&#46; Similar to the IHC results &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2C</a>&#41;&#44; <span class="elsevierStyleItalic">RNPS1</span> was localized in the nucleus&#46; In addition&#44; <span class="elsevierStyleItalic">RNPS1</span> expression was significantly higher in RL952 cells than in other cells &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig2">Figure 2D and E</a>&#41;&#46; Therefore&#44; we used RL952 as the UCEC model cell line associated with <span class="elsevierStyleItalic">RNPS1</span> for further investigation&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia></span><span id="cesec170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle220">Development of UCEC <span class="elsevierStyleItalic">in vitro</span> was regulated after RNPS1 knockdown</span><p id="para200" class="elsevierStylePara elsevierViewall">We knocked down RNPS1 using the lentivirus sh-RNPS1 to verify the role of RNPS1 in UCEC and its correlation with the previously obtained results &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3</a>&#41;&#46; The control&#44; sh-RNPS1&#44; and control-shRNPS1 RL952 cells proliferated &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3A</a>&#41;&#46; However&#44; the optical density of the samples&#44; as detected by MTT&#44; decreased at 3 and 4 days in the sh-RNPS1 group &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#41;&#46; We measured the levels of apoptotic and tumor biomarkers of UCEC to determine their regulation after RNPS1 knockdown &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3B</a>&#41;&#46; The levels of CEA&#44; CA199&#44; CA153&#44; HE4&#44; and Bcl-2 were reduced&#44; whereas the activities of Bax and cleaved caspase-3 were induced in the sh-RNPS1 group &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig3">Figure 3C</a>&#41;&#46;</p><elsevierMultimedia ident="fig3"></elsevierMultimedia></span><span id="cesec180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle230">Development of UCEC <span class="elsevierStyleItalic">in vivo</span> was regulated after RNPS1 knockdown</span><p id="para210" class="elsevierStylePara elsevierViewall">As <span class="elsevierStyleItalic">RNPS1</span> knockdown regulated the progress of UCEC <span class="elsevierStyleItalic">in vitro</span>&#44; we examined whether this also occurred <span class="elsevierStyleItalic">in vivo</span> &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4</a>&#41;&#46; We found that the tumor volumes of the sh-RNPS1 mice were significantly decreased at 21 and 28 days &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig4">Figure 4A</a>&#41;&#44; and the level of <span class="elsevierStyleItalic">RNPS1</span> and the proliferation index&#44; Ki-67&#44; were reduced &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4B</a>&#41;&#46; We assessed the levels of apoptotic and tumor biomarkers in UCECs &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4C</a>&#41;&#46; The levels of CEA&#44; CA199&#44; CA153&#44; HE4&#44; and Bcl-2 decreased&#44; while those of Bax and cleaved caspase-3 increased &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig4">Figure 4F</a>&#41;&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia></span><span id="cesec190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle240">Bioinformatic analyses of the functions of RNPS1 in MSI and MMR in UCEC by pan-cancer&#44; GSEA&#44; and correlation analysis</span><p id="para220" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig5">Figure 5A</a> shows the functions of <span class="elsevierStyleItalic">RNPS1</span> and MSI in different types of cancer&#46; We found that <span class="elsevierStyleItalic">RNPS1</span> was positively associated with MSI in the UCEC&#46; The GSEA results showed that <span class="elsevierStyleItalic">RNPS1</span> was negatively for MMR &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5B</a>&#41;&#46; Correlation analysis verified that <span class="elsevierStyleItalic">RNPS1</span> was negatively correlated with the MMR markers <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> but positively correlated with <span class="elsevierStyleItalic">MSH1</span> and <span class="elsevierStyleItalic">PMS2</span> in UCEC &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5B</a>&#41;&#46;</p><elsevierMultimedia ident="fig5"></elsevierMultimedia></span><span id="cesec200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle250">MMR marker levels were increased by RNPS1 knockdown <span class="elsevierStyleItalic">in vivo</span></span><p id="para230" class="elsevierStylePara elsevierViewall">As previous predictions have indicated that the <span class="elsevierStyleItalic">RNPS1</span> gene is associated with MSI and MMR in UCEC&#44; we examined MMR marker levels <span class="elsevierStyleItalic">in vivo</span>&#46; <a class="elsevierStyleCrossRef" href="#fig6">Figure 6A</a> shows the increased expression of <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> in the sh-RNPS1 group &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#41; compared with the other groups &#40;<a class="elsevierStyleCrossRef" href="#fig6">Figure 6B</a>&#41;&#46;</p><elsevierMultimedia ident="fig6"></elsevierMultimedia></span><span id="cesec210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle260">Mismatch repair was regulated by RNPS1 knockdown through Notch signaling pathway <span class="elsevierStyleItalic">in vivo</span></span><p id="para240" class="elsevierStylePara elsevierViewall">The GSEA findings showed that <span class="elsevierStyleItalic">RNPS1</span> was positively for Notch&#44; especially&#44; Notch4 signaling &#40;<a class="elsevierStyleCrossRef" href="#fig7">Figure 7A</a>&#41;&#46; To confirm this&#44; we blocked Notch expression using an inhibitor of Mastermind Recruitment-1A &#40;IMR-1A&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig7">Figure 7B</a> shows that IMR-1A decreased the levels of <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> after <span class="elsevierStyleItalic">RNPS1</span> knockdown &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#41; compared with the case in the sh-RNPS1 group &#40;<a class="elsevierStyleCrossRef" href="#fig7">Figure 7C</a>&#41;&#59; notably&#44; IMR-1A reduced the <span class="elsevierStyleItalic">RNPS1</span> levels&#46;</p><elsevierMultimedia ident="fig7"></elsevierMultimedia></span><span id="cesec220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle270">Further bioinformatics analysis of RNPS1 in patients with UCEC using target gene assays</span><p id="para250" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig8">Figure S1</a> shows the results of the target gene assays of <span class="elsevierStyleItalic">RNPS1</span> in UCEC tissues&#46; Mutations were found in the group with higher levels of <span class="elsevierStyleItalic">RNPS1&#44; NAA11&#44; C2orf57&#44; NUPR1&#44; GPR157&#44; GTF2H2C&#44; NXNL1&#44; SNCB&#44; FAM177B&#44; RAB29&#44; BCL2L12&#44; PRPH&#44;</span> and <span class="elsevierStyleItalic">WDR74</span>&#46; These results suggest that <span class="elsevierStyleItalic">RNPS1</span> is associated with these gene mutations and participates in the prognosis of UCEC&#46;</p><elsevierMultimedia ident="fig8"></elsevierMultimedia></span></span><span id="cesec230" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle280">DISCUSSION</span><p id="para260" class="elsevierStylePara elsevierViewall">Endometrioid EC is the most common uterine malignancy&#44; with a mortality rate of approximately 20&#37;&#59; it is the most prevalent gynecological malignancy in western and developed countries &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#44;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41;&#46; The mortality rates of endometrioid EC are increasing&#44; indicating the need for more effective diagnostic and treatment strategies &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#41;&#46; MMR deficiency due to the loss of MMR protein expression&#44; a hotspot mutation in the POLE exonuclease domain&#44; and a nonspecific molecular profile may be prognostic factors for patients with advanced UCEC &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#44;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#41;&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">A recent whole-genome analysis found that <span class="elsevierStyleItalic">RNPS1</span> regulates carcinogenesis&#44; especially&#44; in EC &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46; As little is known about <span class="elsevierStyleItalic">RNPS1</span>&#44; it should be a hot topic in oncological research&#46; In the present study&#44; bioinformatics and molecular biological methods were applied to determine the functions of <span class="elsevierStyleItalic">RNPS1</span> in UCEC&#46; Higher levels of <span class="elsevierStyleItalic">RNPS1</span> are expressed in UCEC tumors than in normal tissues&#59; the prognostic outcomes of patients with UCEC were poor&#44; and abundant expression of the <span class="elsevierStyleItalic">RNPS1</span> isoform were observed&#46; These results showed that <span class="elsevierStyleItalic">RNPS1</span> may be an oncogene involved in the prognosis of UCEC&#46; To verify this issue&#44; we compared the levels of the <span class="elsevierStyleItalic">RNPS1</span> protein in various tissues and cell lines&#46; The results showed that <span class="elsevierStyleItalic">RNPS1</span> expression was increased in EC tissue and RL952 cells&#44; consistent with the findings of the bioinformatics analyses&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">Apoptosis is a programmed cell death that does not elicit an inflammatory response &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&#46; Knocking down RNPS1 weakened tumor cell proliferation and biomarkers&#44; reduced tumor volume&#44; increased apoptosis <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; and inhibited UCEC development in our study&#46; These results showed that RNPS1 could regulate apoptosis and tumor progression in UCEC and were consistent with the findings of the bioinformatics analyses&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">We further explored the mechanism underlying the action of RNPS1 in EC using bioinformatics methods and found that RNPS1 correlated positively with MSI and negatively with MMR proteins&#44; especially&#44; <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span>&#46; Western blotting confirmed the bioinformatic findings of a relationship between RNPS1 and MMR&#44; as the <span class="elsevierStyleItalic">RNPS1</span> knockdown lentivirus improved the expression of <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> but not <span class="elsevierStyleItalic">MSH1</span> and <span class="elsevierStyleItalic">PMS2</span>&#46; We plan to report this issue&#44; but some methodological deficiencies resulting from limited laboratory conditions prevent more rigorous and advanced experimentation&#46; Other scholars should investigate these findings further&#46;</p><p id="para300" class="elsevierStylePara elsevierViewall">Clonal diversity was due to the accumulation of mutations in genes of diverse pathways&#44; such as Notch and MMR pathways &#40;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41;&#46; Notch signaling can provide the first mechanistic example of altered glycosylation in tumor cells with MSI &#40;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#41;&#46; Our GSEA findings showed that <span class="elsevierStyleItalic">RNPS1</span> correlated positively with Notch signaling&#44; especially&#44; the Notch4 signaling pathway in UCEC&#46; We investigated this aspect by blocking Notch signaling using IMR-1A&#46; The results showed that IMR-1A decreased <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> levels after lentivirus-based <span class="elsevierStyleItalic">RNPS1</span> knockdown&#46; Furthermore&#44; IMR-1A reduced the <span class="elsevierStyleItalic">RNPS1</span> levels&#44; suggesting that Notch is an upstream factor for <span class="elsevierStyleItalic">RNPS1</span>&#46; However&#44; as a specific Notch4 inhibitor is not yet available&#44; we could only inhibit Notch signaling&#46; The present results showed that <span class="elsevierStyleItalic">RNPS1</span> may be a downstream target factor of Notch&#59; therefore&#44; the Notch4 signaling pathway may regulate MMR in UCEC&#46;</p><p id="para310" class="elsevierStylePara elsevierViewall">Bioinformatic analyses of <span class="elsevierStyleItalic">RNPS1</span> in patients with UCEC using the target gene system showed that <span class="elsevierStyleItalic">RNPS1</span> may be associated with mutations in <span class="elsevierStyleItalic">NAA11&#44; C2orf57&#44; NUPR1&#44; GPR157&#44; GTF2H2C&#44; NXNL1&#44; SNCB&#44; FAM177B&#44; RAB29&#44; BCL2L12&#44; PRPH&#44;</span> and <span class="elsevierStyleItalic">WDR74</span>&#44; participating in UCEC prognosis&#46; These data await confirmation in future investigations and will be the focus of our subsequent studies&#46;</p><p id="para320" class="elsevierStylePara elsevierViewall">We found that <span class="elsevierStyleItalic">RNPS1</span> knockdown significantly activated apoptosis and inhibited EC development and <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> expression <span class="elsevierStyleItalic">via</span> the Notch signaling pathway&#46; Overall&#44; our findings offer a new strategy for treating UCEC&#46;</p></span><span id="cesec240" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle290">AUTHOR CONTRIBUTIONS</span><p id="para330" class="elsevierStylePara elsevierViewall">Liu X designed the study and manuscript drafting&#46; Ma H and Ma L analyzed the data&#46; Li K wrote and revised the manuscript&#46; Kang Y polished the first manuscript drafting and designed the methodology&#46;</p></span></span>"
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        1 => array:2 [
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          "titulo" => "INTRODUCTION"
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        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
          "secciones" => array:11 [
            0 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "UCEC specimens from patients"
            ]
            1 => array:2 [
              "identificador" => "cesec40"
              "titulo" => "Bioinformatics analysis"
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            2 => array:2 [
              "identificador" => "cesec50"
              "titulo" => "Cell lines and cell culture"
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            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Animals"
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            4 => array:2 [
              "identificador" => "cesec70"
              "titulo" => "Antibodies"
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            5 => array:2 [
              "identificador" => "cesec80"
              "titulo" => "RNPS1-knockdown lentivirus administration"
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            6 => array:2 [
              "identificador" => "cesec90"
              "titulo" => "UCEC mouse model"
            ]
            7 => array:2 [
              "identificador" => "cesec100"
              "titulo" => "Western blotting"
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            8 => array:2 [
              "identificador" => "cesec110"
              "titulo" => "Immunohistochemistry &#40;IHC&#41;"
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            9 => array:2 [
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              "titulo" => "MTT assay"
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              "titulo" => "Statistical analysis"
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          "titulo" => "RESULTS"
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              "identificador" => "cesec150"
              "titulo" => "Identifying the potential function of RNPS1 in UCEC using bioinformatics analysis"
            ]
            1 => array:2 [
              "identificador" => "cesec160"
              "titulo" => "Different levels of RNPS1 in tissues or cell lines of UCEC"
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            2 => array:2 [
              "identificador" => "cesec170"
              "titulo" => "Development of UCEC in vitro was regulated after RNPS1 knockdown"
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              "identificador" => "cesec180"
              "titulo" => "Development of UCEC in vivo was regulated after RNPS1 knockdown"
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              "identificador" => "cesec190"
              "titulo" => "Bioinformatic analyses of the functions of RNPS1 in MSI and MMR in UCEC by pan-cancer&#44; GSEA&#44; and correlation analysis"
            ]
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              "identificador" => "cesec200"
              "titulo" => "MMR marker levels were increased by RNPS1 knockdown in vivo"
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              "identificador" => "cesec210"
              "titulo" => "Mismatch repair was regulated by RNPS1 knockdown through Notch signaling pathway in vivo"
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              "identificador" => "cesec220"
              "titulo" => "Further bioinformatics analysis of RNPS1 in patients with UCEC using target gene assays"
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          "titulo" => "DISCUSSION"
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    "fechaRecibido" => "2021-07-15"
    "fechaAceptado" => "2021-09-21"
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            0 => "RNPS1"
            1 => "UCEC"
            2 => "MMR"
            3 => "Proliferation"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVE&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">To determine the role of RNA-binding protein with serine-rich domain 1 &#40;<span class="elsevierStyleItalic">RNPS1</span>&#41; in uterine corpus endometrial carcinoma &#40;UCEC&#41;&#44; the role of <span class="elsevierStyleItalic">RNPS1</span> knockdown in UCEC development <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; and the relationship between <span class="elsevierStyleItalic">RNPS1</span> and mismatch repair &#40;MMR&#41; in UCEC&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">We predicted the potential function of <span class="elsevierStyleItalic">RNPS1</span> using bioinformatics systems&#46; The expression of <span class="elsevierStyleItalic">RNPS1</span> in tissues and cell lines was analyzed by western blotting and immunohistochemistry&#46; The expression of <span class="elsevierStyleItalic">RNPS1</span> in MMR was assessed using bioinformatics and western blotting&#46; The proliferation and apoptosis of UCEC cells were assessed under <span class="elsevierStyleItalic">RNPS1</span> knockdown conditions&#44; and <span class="elsevierStyleItalic">RNPS1</span> regulation in MMR was detected by suppressing Notch signaling&#46; Associations between <span class="elsevierStyleItalic">RNPS1</span> and gene mutations in UCEC and prognosis were analyzed&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">The <span class="elsevierStyleItalic">RNPS1</span> level was higher in UCEC tumors than in normal tissues and tumors or RL952 cells&#46; Prognostic outcomes were worse when UCEC showed abundant <span class="elsevierStyleItalic">RNPS1</span> expression&#46; Lentiviral <span class="elsevierStyleItalic">RNPS1</span> knockdown weakened tumor cell proliferation and suppressed biomarker expression&#44; reduced the tumor volume&#44; promoted apoptosis <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; and inhibited UCEC development&#46; Increased MutS homolog 2 &#40;<span class="elsevierStyleItalic">MSH2</span>&#41; and MutS homolog 6 &#40;<span class="elsevierStyleItalic">MSH6</span>&#41; levels in MMR after <span class="elsevierStyleItalic">RNPS1</span> knockdown were reversed by inhibiting Notch signaling&#46; Furthermore&#44; <span class="elsevierStyleItalic">RNPS1</span> was associated with mutations in <span class="elsevierStyleItalic">NAA11</span>&#44; <span class="elsevierStyleItalic">C2orf57</span>&#44; <span class="elsevierStyleItalic">NUPR1</span>&#44; and other genes involved in UCEC prognosis&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara120" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">RNPS1</span> may regulate the expression levels of <span class="elsevierStyleItalic">MSH2</span> and <span class="elsevierStyleItalic">MSH6</span> in MMR&#44; enhancing the proliferation&#44; development&#44; and prognosis of UCEC through a Notch signaling pathway in UCEC&#46; Our study offers a new method and strategy for delaying UCEC development through modulating MMR&#46;</p></span>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Assessment of <span class="elsevierStyleItalic">RNPS1</span> expression in cancers&#46; &#40;B&#41; GSEA of the correlation between <span class="elsevierStyleItalic">RNPS1</span> and UCEC&#46; &#40;C&#41; OS and &#40;D&#41; RFS analyses of the role of <span class="elsevierStyleItalic">RNPS1</span> in UCEC patients&#46;</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; <span class="elsevierStyleItalic">RNPS1</span> expression&#44; &#40;B&#41; quantitation of the <span class="elsevierStyleItalic">RNPS1</span> expression levels from the western blots&#44; and &#40;C&#41; IHC staining analysis for <span class="elsevierStyleItalic">RNPS1</span> in para-tumor and tumor tissues &#40;&#215;400&#41;&#46; &#40;D&#41; <span class="elsevierStyleItalic">RNPS1</span> expression in NEC&#44; KLE&#44; RL952&#44; Ishikawa&#44; and ECC-1 cells&#46; &#40;E&#41; Quantitation of the <span class="elsevierStyleItalic">RNPS1</span> expression levels in cells&#46; Protein levels were normalized to those of &#946;-actin&#46; &#40;n&#61;6&#44; &#42;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; tumor <span class="elsevierStyleItalic">vs&#46;</span> para-tumor or RL952 <span class="elsevierStyleItalic">vs&#46;</span> other cells&#41;&#46;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Proliferation assays of cells from the Con&#44; sh-RNPS1&#46; and control-shRNPS1 groups at 4 days&#46; &#40;B&#41; Western blots for the analysis of the levels of CEA&#44; CA199&#44; CA153&#44; HE4&#44; Bax&#44; Bcl-2&#46; and cleaved caspase-3&#46; &#40;C&#41; Quantitation of the levels of CEA&#44; CA199&#44; CA153&#44; HE4&#44; Bcl-2&#44; Bax&#44; and cleaved caspase-3&#46; &#40;n&#61;6&#44; &#42;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; sh-RNPS1 <span class="elsevierStyleItalic">vs&#46;</span> other groups&#41;&#46;</p>"
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          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Tumor volume in mice from the Con&#44; sh-RNPS1&#44; and control-shRNPS1 groups at 28 days&#46; &#40;B&#41; IHC analysis for detecting the <span class="elsevierStyleItalic">RNPS1</span> levels and Ki-67 index&#46; &#40;C&#41; Western blots for the analysis of the levels of CEA&#44; CA199&#44; CA153&#44; HE4&#44; Bcl-2&#44; Bax&#44; and cleaved caspase-3&#44; &#40;D&#41; Quantitation of the levels of CEA&#44; CA199&#44; CA153&#44; HE4&#44; Bax&#44; Bcl-2&#44; and cleaved caspase-3&#46; &#40;n&#61;6&#44; &#42;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; sh-RNPS1 <span class="elsevierStyleItalic">vs&#46;</span> other groups&#41;&#46;</p>"
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          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Pan-cancer assays of MSI in different cancers&#46; &#40;B&#41; GSEA of the correlation between <span class="elsevierStyleItalic">RNPS1</span> and MMR in UCEC&#46; &#40;C&#41; Analysis of the correlation of <span class="elsevierStyleItalic">RNPS1</span> with <span class="elsevierStyleItalic">MSH1&#44; MSH2&#44; MSH6&#44;</span> and <span class="elsevierStyleItalic">PMS2</span> in UCEC&#46;</p>"
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          "en" => "<p id="spara60" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Western blots for the analysis of the <span class="elsevierStyleItalic">MSH1&#44; MSH2&#44; MSH6</span>&#44; and <span class="elsevierStyleItalic">PMS2</span> expression levels <span class="elsevierStyleItalic">in vivo</span>&#44; &#40;B&#41; Quantitation of the <span class="elsevierStyleItalic">MSH1&#44; MSH2&#44; MSH6&#44;</span> and <span class="elsevierStyleItalic">PMS2</span> expression levels&#46; &#40;n&#61;6&#44; &#42;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; sh-RNPS1 <span class="elsevierStyleItalic">vs&#46;</span> other groups&#41;&#46;</p>"
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          "en" => "<p id="spara70" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; GSEA of the correlation between <span class="elsevierStyleItalic">RNPS1</span> and Notch or Notch4 signaling pathway in UCEC&#46; &#40;B&#41; Western blot assay for the analysis of the <span class="elsevierStyleItalic">RNPS1&#44; MSH1&#44; MSH2&#44; MSH6&#44;</span> and <span class="elsevierStyleItalic">PMS2</span> expression levels <span class="elsevierStyleItalic">in vivo</span>&#46; &#40;B&#41; Quantitation of <span class="elsevierStyleItalic">RNPS1&#44; MSH1&#44; MSH2&#44; MSH6&#44;</span> and <span class="elsevierStyleItalic">PMS2</span> expression levels&#46; &#40;n&#61;6&#44; &#42;<span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; sh-RNPS1 <span class="elsevierStyleItalic">vs&#46;</span> Con&#59; <span class="elsevierStyleSup">&#35;</span><span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#58; IMR-1A&#43;sh-RNPS1 <span class="elsevierStyleItalic">vs&#46;</span> sh-RNPS1&#41;&#46;</p>"
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">5&#8242;-cgctccagctccaactcctc-3&#8242;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5&#8242;-ataccccacccagctcagtt-3&#8242;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Control-shRNPS1&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Sequences of RNPS1 lentiviruses&#46;</p>"
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          "en" => "<p id="spara130" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Expression of <span class="elsevierStyleItalic">RNPS1</span> in UCEC patients with mutant or wild-type <span class="elsevierStyleItalic">NAA11</span>&#44; <span class="elsevierStyleItalic">C2orf57</span>&#44; <span class="elsevierStyleItalic">NUPR1</span>&#44; <span class="elsevierStyleItalic">GPR157</span>&#44; <span class="elsevierStyleItalic">GTF2H2C</span>&#44; <span class="elsevierStyleItalic">NXNL1</span>&#44; <span class="elsevierStyleItalic">SNCB</span>&#44; <span class="elsevierStyleItalic">FAM177B</span>&#44; <span class="elsevierStyleItalic">RAB29</span>&#44; <span class="elsevierStyleItalic">BCL2L12</span>&#44; <span class="elsevierStyleItalic">PRPH</span>&#44; and <span class="elsevierStyleItalic">WDR74</span>&#46;</p>"
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                      "titulo" => "Identification of a Multi-RNA-Type-Based Signature for Recurrence-Free Survival Prediction in Patients with Uterine Corpus Endometrial Carcinoma"
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                              P Wang \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              Z Zeng \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              X Shen \n
                              \t\t\t\t\t\t\t\t
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                              X Tian \n
                              \t\t\t\t\t\t\t\t
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                              Q Ye \n
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                        "tituloSerie" => "DNA Cell Biol"
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                        "numero" => "4"
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                        "paginaFinal" => "630"
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                              M Akhtar \n
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                              S Al Hyassat \n
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                              O Elaiwy \n
                              \t\t\t\t\t\t\t\t
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                              S Rashid \n
                              \t\t\t\t\t\t\t\t
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                              ADMH Al-Nabet \n
                              \t\t\t\t\t\t\t\t
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                        "paginaFinal" => "427"
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                      "titulo" => "Survival effect of para-aortic lymphadenectomy in endometrial cancer &#40;SEPAL study&#41;&#58; a retrospective cohort analysis"
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                              Y Todo \n
                              \t\t\t\t\t\t\t\t
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                              H Kato \n
                              \t\t\t\t\t\t\t\t
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                              M Kaneuchi \n
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                              H Watari \n
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                              M Takeda \n
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                              E Stelloo \n
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                              RA Nout \n
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                              EM Osse \n
                              \t\t\t\t\t\t\t\t
                              """
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                              IJ Jurgenliemk-Schulz \n
                              \t\t\t\t\t\t\t\t
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Article information
ISSN: 18075932
Original language: English
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