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let-7b-5p suppresses the proliferation and migration of pulmonary artery smooth muscle cells via down-regulating IGF1
Yadi Zhang, Sihui Tang, Wanchun Yang, Fangbing Du
Corresponding author
Dufangbing5445@126.com

Corresponding author.
Department of Respiratory Medicine, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Suppressing let-7b-5p could reinforce PDGF-induced abnormal proliferation and migration of PASMCs&#46; &#40;A&#41; The PCNA protein expression in PASMCs with different treatments detected by western blot&#46; The proliferation of PASMCs with different treatments detected by &#40;B&#41; CCK-8 and &#40;C&#41; Edu assays &#40;scale bar&#160;&#61;&#160;100&#956;m&#41;&#46; &#40;D&#41; Wound healing and &#40;E&#41; Transwell assay detected the migration ability of PASMCs with different treatments&#59; Scale bar&#160;&#61;&#160;100&#956;m&#46; Note&#58; &#42;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#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">With the rapid development of sequencing technology&#44; research on the relation between non-coding RNAs &#40;ncRNAs&#41; and human diseases has increased exponentially in the last decades&#46; Micro RNAs &#40;miRNAs&#41;&#44; a type of ncRNAs with an approximate length of&#160;22&#160;nt&#44; can suppress the transcription or translation of target mRNAs&#44; thereby regulating human physiological and pathological processes&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> To date&#44; the total number of miRNAs identified and validated in the human genome is in excess of&#160;1000&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> For example&#44; miR-222 has been proven to be involved in the modulation of insulin sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Besides&#44; Jiang&#44; et&#160;al&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> demonstrated that miR-130a is capable of improving cardiac function in a heart failure model&#46; Nevertheless&#44; there are still significant gaps in comprehensively understanding the roles of miRNAs since human diseases are diverse and complex&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">As a potentially lethal complication of venous thromboembolism&#44; Pulmonary Embolism &#40;PE&#41; is the obstruction of pulmonary arteries resulting from thrombus migrating from a deep vein in the legs or pelvis&#46; The incidence of PE in the population is obviously associated with age&#59; from&#160;0&#46;14&#37; of people aged&#160;40&#8210;49 to&#160;1&#46;13&#37; of aged&#160;80&#160;years or over&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> With the aging of the global population&#44; the burden of PE is increasing sharply worldwide&#44;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> especially in China&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Understanding the pulmonary pathophysiology of PE at an RNA level is significant in developing efficient management and therapies for PE patients&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">Some previous studies indicated that the excessive proliferation and migration of Pulmonary Artery Smooth Muscle Cells &#40;PASMCs&#41; could be observed in pulmonary artery intima after PE occurred&#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> However&#44; there is a little study reporting the mechanism behind these behaviors of PASMCs&#46; In recent years&#44; some miRNAs have been found to be differentially expressed in the blood of PE patients&#44; which might be used as a diagnostic biomarker for PE&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> Liu&#44; Liu and Kang<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> recently identified three miRNAs that were differentially expressed in blood from PE patients&#44; including let-7a-5p&#44; let-7b-5p&#44; and miR-150-5p&#46; let-7b-5p is a well-studied miRNA&#44; which could suppress cell proliferation and migration in various diseases&#44; including gastric cancer<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> and glioma&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Accordingly&#44; the authors speculated that the abnormal proliferation and migration of PASMCs may be related to the dysregulation of let-7b-5p following PE&#46;</p><p id="para0011" class="elsevierStylePara elsevierViewall">Herein&#44; the authors sought to explore the effect of let-7b-5p on the proliferation and migration of PASMCs and unravel the underlying mechanism&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Cell culture</span><p id="para0012" class="elsevierStylePara elsevierViewall">PASMCs purchased from ATCC &#40;VA&#44; USA&#41; were cultivated in a regular growth medium containing DMEM and 10&#37;&#160;FBS in a humidified environment of&#160;5&#37; CO<span class="elsevierStyleInf">2</span> at&#160;37&#160;&#176;C&#46; After cell confluency reached&#160;80&#8210;90&#37;&#44; cultured cells were digested with&#160;0&#46;25&#37; Trypsin&#44; followed by subculture at a ratio of&#160;1&#58;2&#46; The DMEM&#44; FBS&#44; and 0&#46;25&#37;&#160;Trypsin were purchased from Gibco &#40;NY&#44; USA&#41;&#46; This study has been approved by the Ethics Committee of the Second People&#39;s Hospital of Hefei and Hefei Hospital Affiliated with Auhui Medical University&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Platelet-derived growth factor &#40;PDGF&#41; treatment</span><p id="para0013" class="elsevierStylePara elsevierViewall">PDGF &#40;Sigma-Aldrich&#44; MO&#44; USA&#41; was utilized to establish an abnormal proliferation model in PASMCs&#46; For PDGF treatment&#44; PASMCs were seeded into&#160;96-well plates and incubated for&#160;24&#160;h&#44; followed by incubation with different concentrations of PDGF &#40;0&#44; 10&#44; 20&#44; and 40&#160;ng&#47;mL&#41;&#46; After cultivation for&#160;24h&#44; the proliferation and let-7b-5p expression of cells were measured&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">CCK-8 assay</span><p id="para0014" class="elsevierStylePara elsevierViewall">Treated cells in&#160;96-well plates were gently washed thrice with PBS&#44; and subsequently added with&#160;100&#160;&#956;L CCK-8 reagent diluted in DMEM &#40;1&#58;10&#44; v&#47;v&#41; to further incubate for&#160;2&#160;h&#46; Finally&#44; the absorbance at&#160;450&#160;nm of each well was detected with a Microplate reader &#40;Bio-Rad&#44; CA&#44; USA&#41; to calculate cell viability&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Reverse transcription&#8209;quantitative polymerase chain reaction &#40;RT-qPCR&#41;</span><p id="para0015" class="elsevierStylePara elsevierViewall">The extraction of total RNA from cells and subsequent reverse transcription were carried out according to standard protocols&#46; RT-qPCR analysis was performed on the&#160;7500 Real-Time PCR System &#40;Applied Biosystems&#44; CA&#44; USA&#41; to measure the expression levels of let-7b-5p&#44; IGF1&#44; GAPDH&#44; and U6&#46; GAPDH and U6 were utilized to normalize the expression of IGF1 and let-7b-5p&#44; respectively&#59; and the expressions were analyzed based on the&#160;2<span class="elsevierStyleSup">&#8211;&#916;&#916;Ct</span> method&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> The primer sequences used in this study were described as follows&#58; let-7b-5p &#40;Forward 5&#8217;- GTGAGGTAGTAGGTTGTGTG -3&#8217;&#59; Reverse 5&#8217;- GGTCCAGTTTTTTTTTTTTTTTAACCA-3&#8217;&#41;&#44; IGF1 &#40;Forward 5&#8217;- GCTCTTCAGTTCGTGTGTGGA-3&#8217;&#59; Reverse 5&#8217;- GCCTCCTTAGATCACAGCTCC -3&#8217;&#41;&#44; GAPDH &#40;Forward 5&#8217;- GGAGCGAGATCCCTCCAAAAT- 3&#8217;&#59; Reverse 5&#8217;- GGCTGTTGTCATACTTCTCATGG-3&#8217;&#41;&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Cell transfection</span><p id="para0016" class="elsevierStylePara elsevierViewall">The let-7b-5p mimic&#44; inhibitor&#44; and their corresponding negative control &#40;NC mimic and NC inhibitor&#41;&#44; the IGF1 overexpression vector&#44; and blank vector were utilized in this study&#46; Briefly&#44; cells were seeded in plates for&#160;24&#160;h incubation prior to transfection&#46; The transfection in cells was performed with Lipofectamine&#174; 2000&#160;reagent &#40;Invitrogen&#44; CA&#44; USA&#41; mixed with different plasmids&#46; After&#160;48h transfection&#44; transfected cells were harvested to assess the transfection efficiency by RT-qPCR&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Western blot &#40;WB&#41;</span><p id="para0017" class="elsevierStylePara elsevierViewall">Total protein of cells was extracted using RIPA buffer &#40;Abcam&#44; MA&#44; USA&#41;&#44; followed by quantified with a BCA Kit &#40;Beyotime&#44; Shanghai&#44; China&#41;&#46; Western blot analysis was conducted as reported by Mahmood and Yang&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> Briefly&#44; the proteins were separated by SDS-PAGE gel before being transferred onto a PVDF membrane&#46; Then&#44; the membrane was blocked with skimmed milk for&#160;1&#46;5&#160;h&#44; followed by incubated with primary antibodies overnight and secondary antibodies for&#160;2h&#46; Finally&#44; protein bands were visualized by ECL Substrate Kit &#40;Abcam&#44; MA&#44; USA&#41;&#44; and quantified using Image J software&#46; The antibodies used in this study were all purchased from Abcam &#40;MA&#44; USA&#41;&#44; of which dilutions were as follows&#58; proliferating cell nuclear antigen &#40;PCNA&#41; &#40;&#35;ab29&#44; 1&#58;2000&#41;&#44; GAPDH &#40;&#35;ab8245&#44; 1&#58;8000&#41;&#44; IGF1 &#40;&#35;ab134140&#44; 1&#58;20000&#41;&#44; and Goat Anti-Rabbit IgG H&#38;L &#40;HRP&#41; &#40;&#35;ab6721&#44; 1&#58;3000&#41;&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Ethynyl deoxyuridine &#40;Edu&#41; assay</span><p id="para0018" class="elsevierStylePara elsevierViewall">EdU Staining Proliferation Kit &#40;Abcam&#44; MA&#44; USA&#41; was utilized to evaluate the proliferation of transfected cells in different groups according to protocols provided by the manufacturer&#46; Briefly&#44; transfected cells were incubated with Edu overnight&#44; then fixed and stained&#46; Cell nuclei were stained with DAPI &#40;Invitrogen&#44; CA&#44; USA&#41; for&#160;15&#160;min prior to observing and counting EdU-positive cells under a BX51 microscope &#40;Olympus&#44; Tokyo&#44; Japan&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Wound healing assay</span><p id="para0019" class="elsevierStylePara elsevierViewall">A total of&#160;2&#215;10<span class="elsevierStyleSup">5</span>&#160;transfected cells were seeded into each well of six-well plates and cultured until a monolayer of cells had formed&#46; The&#160;200&#160;&#956;L pipette tip was used to create similar size of scratches in the cell layer for each group&#46; Next&#44; scratched cells were removed by gently rinsing PBS thrice&#59; the remaining cells were continually cultured for&#160;24&#160;h&#46; After scratching for&#160;0&#160;and&#160;24&#160;h&#44; the wound of each well was photographed with a BX51 microscope&#59; and the migrated area was calculated to evaluate cell migration ability&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Transwell migration assay</span><p id="para0020" class="elsevierStylePara elsevierViewall">The migration of transfected cells was also assessed by Transwell chambers &#40;Corning&#44; NY&#44; USA&#41;&#46; In brief&#44; 700&#160;&#956;L DMEM with serum was added to the lower chamber&#46; Meanwhile&#44; transfected cells were plated on the upper chambers containing&#160;200&#160;&#956;L DMEM for&#160;24&#160;h incubation&#46; 24&#160;h&#160;later&#44; cells still in the upper chamber were wiped out&#44; while cells traversing the membranes to the lower chamber were fixed in&#160;4&#37; paraformaldehyde prior to the staining of&#160;0&#46;1&#37; crystal violet&#46; The stained cells were imaged and counted in five random visual fields under a BX51 microscope&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Bioinformatics prediction</span><p id="para0021" class="elsevierStylePara elsevierViewall">ENCORI &#40;The Encyclopedia of RNA Interactomes&#41;&#44; which is also known as starbase&#44; &#40;<a href="http://starbase.sysu.edu.cn">http&#58;&#47;&#47;starbase&#46;sysu&#46;edu&#46;cn</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> was utilized to predict the potential target genes of let-7b-5p&#46;</p><p id="para0022" class="elsevierStylePara elsevierViewall">Metascape &#40;<a href="https://metascape.org">https&#58;&#47;&#47;metascape&#46;org</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> was applied to perform the functional annotation of predicted genes&#46; Afterward&#44; the predicted genes associated with &#8220;positive regulation of smooth muscle cell proliferation&#8221;&#44; &#8220;positive regulation of smooth muscle cell migration&#8221;&#44; &#8220;smooth muscle cell migration&#8221;&#44; and &#8220;regulation of smooth muscle cell migration&#8221; were intersected to obtain objective gene&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Dual-luciferase assay</span><p id="para0023" class="elsevierStylePara elsevierViewall">To construct the luciferase reporter vector&#44; the 3&#8217;UTR &#40;wildtype&#44; WT or mutated control&#44; MUT&#41; of the IGF1 cDNA fragments incorporating the putative let-7b-5p junction site were amplified to insert into the upstream of the reporter gene in the pmirGlo dual-luciferase vector &#40;Addgene&#44; MA&#44; USA&#41;&#46; For luciferase assay&#44; 293T&#160;cells cultured in a&#160;24-well plate were co-transfected with the constructed vectors &#40;IGF1 3&#8217;UTR WT&#47;MUT&#41; containing firefly luciferase and let-7b-5p mimics or the negative control &#40;NC mimics&#41;&#46; After transfection&#44; the Firefly fluorescence was normalized to the Renilla fluorescence to calculate the luciferase activity&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Ago2 pull down</span><p id="para0024" class="elsevierStylePara elsevierViewall">By using a Magna RIP Kit &#40;Millipore&#44; MA&#44; USA&#41;&#44; the Ago2 pull-down assay was carried out following the guidelines provided by manufacturers&#46; Cells were lysed&#44; and then immunoprecipitated with magnetic beads conjugated with antibodies against Ago2 &#40;&#35;ab32381&#44; Abcam&#44; MA&#44; USA&#41;&#46; Immunoprecipitated RNA was analyzed qRT-PCR&#46; IgG was served as a negative control&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Statistical analysis</span><p id="para0025" class="elsevierStylePara elsevierViewall">All statistical analysis was carried out on GraphPad Prism&#160;8&#46;0&#46;1&#46; In this study&#44; all experiments were repeated at least thrice&#44; and all data were presented as mean&#160;&#177;&#160;Standard Deviation &#40;SD&#41;&#46; A students&#8217; test or one-way ANOVA with post-hoc test &#40;Bonferroni&#41; was performed to analyze the discrepancy among the groups&#46; It is considered to be statistically discrepant when <span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#46;</p></span></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">Results</span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">PDGF induces PASMCs abnormal proliferation with concomitantly decreasing let-7b-5p expression in PASMCs</span><p id="para0026" class="elsevierStylePara elsevierViewall">To study the relation of let-7b-5p expression with cell proliferation in PASMCs&#44; the expression level of let-7b-5p was detected following treatment with different doses of PDGF in PASMCs&#46; Compared with the control group &#40;0&#160;ng&#47;mL PDGF&#41;&#44; the proliferation of PASMCs was promoted by PDGF in a dose-dependent way &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46;&#160;1</a>A&#41;&#46; However&#44; the expression level of let-7b-5p expression was decreased under the administration of PDGF &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46;&#160;1</a>B&#41;&#46; Among diverse concentrations&#44; 40&#160;ng&#47;mL of PDGF exhibited the strongest suppression effect on let-7b-5p expression&#46; Hence&#44; the authors chose the&#160;40&#160;ng&#47;mL as the optimal concentration for the subsequent experiments&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">PDGF-induced abnormal proliferation and migration of PASMCs were antagonized by let-7b-5p mimics&#44; reinforced by let-7b-5p inhibitor</span><p id="para0027" class="elsevierStylePara elsevierViewall">To better understand the role of let-7b-5p on abnormal proliferation and migration of PASMCs&#44; let-7b-5p mimics or let-7b-5p inhibitor was utilized to transfect into PASMCs&#46; RT-qPCR analysis verified the successful transfection of let-7b-5p mimics and let-7b-5p inhibitor in PASMCs &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia><p id="para0028" class="elsevierStylePara elsevierViewall">Compared with the control group&#44; the expression levels of PCNA in PASMCs were obviously elevated by the treatment of PDGF&#46; Notably&#44; the increased expression levels of PCNA induced by PDGF were blocked by the transfection of let-7b-5p mimics &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>B&#41;&#46; Consistent with previous results&#44; PDGF treatment significantly increased the proliferation of PASMCs which was almost reversed by the transfection of let-7b-5p mimics&#44; as confirmed by CCK-8 and Edu assays &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>C and D&#41;&#46; Moreover&#44; both wound healing and Transwell assays showed that the treatment of PDGF remarkably induced the migration of PASMCs which could be blocked by the transfection of let-7b-5p mimics &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>E and F&#41;&#46; These results suggested the suppression role of let-7b-5p on the abnormal proliferation and migration of PASMCs induced by PDGF&#46;</p><p id="para0029" class="elsevierStylePara elsevierViewall">The results of experiments regarding let-7b-5p inhibitor corroborated the above findings &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>&#41;&#46; As shown by PCNA detection&#44; CCK-8&#44; and Edu assays&#44; the promotion of PDGF on cell proliferation in PASMCs was significantly strengthened by the transfection of let-7b-5p inhibitor &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>A-C&#41;&#46; Besides&#44; wound healing and Transwell assays indicated that the transfection of let-7b-5p inhibitor also markedly potentiated the promotion of PDGF on migration in PASMCs &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>D and E&#41;&#46; Hence&#44; let-7b-5p could reverse the aberrant proliferation and migration of PASMCs induced by PDGF&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">let-7b-5p directly interacts with IGF1&#44; and down-regulates the expression of IGF1</span><p id="para0030" class="elsevierStylePara elsevierViewall">To uncover the mechanism behind the effects of let-7b-5p on PASMCs&#44; the target genes of let-7b-5p were identified by bioinformatics tools&#46; A total of&#160;31&#160;potential target genes predicted by starbase were uploaded to Metascape to conduct functional annotation&#46; Then&#44; the genes overlapped in the functional terms of &#8220;positive regulation of smooth muscle cell proliferation&#8221;&#44; &#8220;positive regulation of smooth muscle cell migration&#8221;&#44; &#8220;smooth muscle cell migration&#8221;&#44; and &#8220;regulation of smooth muscle cell migration&#8221; were obtained&#44; including IGF1&#44; PAK1&#44; PDGFB&#44; and ADAMTS1 &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>A&#41;&#46; Given that IGF1 has been reported to be involved in the regulation of PASMCs proliferation&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Hence&#44; IGF1 was chosen as the studied object for further analysis&#46; Dual-luciferase assay was performed to confirm the relation between let-7b-5p and IGF1&#46; The potential binding sites between let-7b-5p and IGF1 were depicted in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>B&#46; Dual-luciferase assay verified that let-7b-5p reduced the luciferase activity of the IGF1 wild-type group&#44; but not the IGF1 mutant group &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>C&#41;&#46; Ago2 pull-down assay further confirmed that IGF1 could spatially interact with let-7b-5p via Ago2 protein &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>D&#41;&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia><p id="para0031" class="elsevierStylePara elsevierViewall">Afterward&#44; the authors also investigated the effect of let-7b-5p on IGF1expression in PASMCs&#46; Compared with the control group&#44; the transfection of let-7b-5p mimics observably reduced the expression of IGF1 in PASMCs&#44; while the let-7b-5p inhibitor exerted the converse effect &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>E&#41;&#46; These results revealed that let-7b-5p directly interacts with IGF1&#44; and further down-regulating the expression of IGF1 in PASMCs&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">IGF1 functions as a target of let-7b-5p on the proliferation and migration of PASMCs</span><p id="para0032" class="elsevierStylePara elsevierViewall">To further investigate whether the inhibitory effect of let-7b-5p on PDGF-induced proliferation and migration of PASMCs was mediated by IGF1&#44; the IGF1 overexpression vector was transfected into PASMCs alone or combined with let-7b-5p before treating PASMCs with PDGF&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>A&#44; IGF1 overexpression significantly increased PCNA expression in PDGF-induced PASMCs&#44; whereas this effect was greatly attenuated by the introduction of let-7b-5p mimics &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>A&#41;&#46; CCK-8 and Edu results showed that overexpressing IGF1 significantly promoted the proliferation of PDGF-induced PASMCs&#44; which was countered after co-transfected with let-7b-5p mimics &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>B and C&#41;&#46; The overexpression of IGF1 also strengthened the migration ability of PDGF-induced PASMCs &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>D and E&#41;&#46; However&#44; the effect of IGF1 overexpression on PDGF-induced PASMCs migration was substantially suppressed by let-7b-5p mimics &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>D and E&#41;&#44; suggesting that let-7b-5p is involved in the migration of PDGF-induced PASMCs mediated by IGF1&#46; These results revealed that let-7b-5p up-regulation blocked IGF1-mediated promotion of proliferation and migration in PDGF-induced PASMCs&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Discussion</span><p id="para0033" class="elsevierStylePara elsevierViewall">A growing number of research revealed that the excessive cellular proliferation and enhancing migration ability of PASMCs are associated with the pulmonary vasoconstriction and remodeling following PE&#46;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a>&#46; Here&#44; the authors reported that let-7b-5p is able to suppress the excessive proliferation and migration of PDGF-induced PASMCs via targeting IGF1&#46;</p><p id="para0034" class="elsevierStylePara elsevierViewall">PDGF is known as a polypeptide growth factor that regulates cell growth and division&#44; and has been identified as a major mitogen for smooth muscle cells&#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> It has been reported that the up-regulation of PDGF is closely related to the progression of PE&#44; such as pulmonary hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> In this study&#44; PDGF was utilized to stimulate PASMCs <span class="elsevierStyleItalic">in vitro</span>&#46; Consistent with previous studies&#44;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> the present data showed that PDGF significantly promoted proliferation in a dose-dependent way&#46; Notably&#44; the expression levels of let-7b-5p in PASMCs decreased with the increase of PDGF concentration&#44; which suggested that let-7b-5p may be involved in the abnormal proliferation of PASMCs&#46; Research on the pathology of multiple cancers has indicated that let-7b-5p plays an inhibitory role in tumorigenesis&#46; Xu&#44; et&#160;al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> revealed that let-7b-5p could significantly suppress the malignant phenotype of multiple myeloma cells&#46; Huang&#44; et&#160;al&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> indicated that let-7b-5p could repress cell proliferation and invasion&#44; as well as the tumor formation of castration-resistant prostate cancer&#46; Accordingly&#44; the authors suppose that let-7b-5p participates in the abnormal proliferation and migration of PASMCs&#46; In line with our assumption&#44; both CCK-8 and Edu assays revealed that the excessive proliferation of PDGF-induced PASMCs was potently countered by overexpressing let-7b-5p&#44; while reinforced by silencing let-7b-5p&#46; As known&#44; PCNA is a standard marker commonly utilized to assess cell proliferation since its critical role in DNA replication&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> The authors subsequently detected the PCNA expression levels in PASMCs from each group&#44; with results that validated the finding above&#46; Moreover&#44; wound healing and Transwell migration assays demonstrated the overexpression of let-7b-5p reversed the promoting migration effect of PDGF in PASMCs&#46; Conversely&#44; the deletion of let-7b-5p aggravated the effect of PDGF on the migration of PASMCs&#46; Combined with the above results&#44; the present study indicated that let-7b-5p is capable of impeding PDGF-induced abnormal proliferation and migration in PASMCs&#46;</p><p id="para0035" class="elsevierStylePara elsevierViewall">It has been widely reported that miRNAs have major effects on multiple biological processes&#44; including cell proliferation&#44; development&#44; and apoptosis&#44; by regulating target genes at the post-transcriptional level&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> Thus&#44; the authors subsequently predicted the potential target of let-7b-5p using bioinformatics online tools to understand the mechanism behind its inhibitory role in the proliferation and migration of PDGF-induced PASMCs&#46; Then&#44; a total of four genes were identified as potential target genes of let-7b-5p that are involved in the biological process of PASMCs&#44; which included IGF1&#44; PAK1&#44; PDGFB&#44; and ADAMTS1&#46; IGF1 is a known mitogen that can be found in most cell types&#44; including smooth muscle cells&#46; Several studies reported that IGF1 plays a crucial role in regulating the proliferation of vascular smooth muscle cells&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> Besides&#44; a previous study demonstrated that IGF1 played an anti-apoptosis effect on PASMCs&#44; thereby promoting the accumulation of PASMCs during pulmonary arterial hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> Based on these&#44; the authors finally selected IGF1 as the studied target of let-7b-5p for further analysis&#46; As expected&#44; the present study confirmed that let-7b-5p directly interacted with the 3&#8217;-UTR of IGF1 to suppress the expression of IGF1 in PASMCs&#46; In the present study&#44; the overexpression of IGF1 promoted the proliferation and motility of PASMCs&#44; consistent with the known function of IGF1 in vascular smooth muscle cells&#46; Additionally&#44; such effects of IGF1 overexpression on the proliferation and migration of PASMCs were observably restrained when co-transfected with let-7b-5p mimics&#44; further indicating that the suppression role of let-7b-5p on the excessive proliferation and migration of PASMCs was exerted by targeting IGF1&#46; Collectively&#44; the present study facilitates an understanding of the effects of let-7b-5p on PASMCs and the mechanism by which let-7b-5p against the aberrant proliferation and migration of PASMCs induced by PDGF&#46; However&#44; it should be acknowledged that the major limitation of this study is lacking validation of the effect of let-7b-5p in the progression of PE <span class="elsevierStyleItalic">in vivo</span>&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">In summary&#44; the present study first reveals the suppression role of let-7b-5p on the abnormal proliferation and migration of PASMCs induced by PDGF and found that IGF1 serves as the downstream effector in this process&#46; The authors hope that the present findings could improve the understanding of pathogenesis and the development of novel therapeutic targets in PE&#46;</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Authors&#39; contributions</span><p id="para0037" class="elsevierStylePara elsevierViewall">Yadi Zhang and Fangbing Du conceived the project&#44; and designed the experiments&#46; Yadi Zhang&#44; Sihui Tang&#44; Wanchun Yang&#44; and Fangbing Du performed the experiments&#44; and analyzed the data&#46; Yadi Zhang and Fangbing Du wrote and revised the manuscript&#46;</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Funding</span><p id="para0038" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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            0 => array:2 [
              "identificador" => "sec0003"
              "titulo" => "Cell culture"
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            1 => array:2 [
              "identificador" => "sec0004"
              "titulo" => "Platelet-derived growth factor &#40;PDGF&#41; treatment"
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              "identificador" => "sec0005"
              "titulo" => "CCK-8 assay"
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              "titulo" => "Reverse transcription&#8209;quantitative polymerase chain reaction &#40;RT-qPCR&#41;"
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              "titulo" => "Cell transfection"
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              "titulo" => "Ethynyl deoxyuridine &#40;Edu&#41; assay"
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              "titulo" => "Wound healing assay"
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            8 => array:2 [
              "identificador" => "sec0011"
              "titulo" => "Transwell migration assay"
            ]
            9 => array:2 [
              "identificador" => "sec0012"
              "titulo" => "Bioinformatics prediction"
            ]
            10 => array:2 [
              "identificador" => "sec0013"
              "titulo" => "Dual-luciferase assay"
            ]
            11 => array:2 [
              "identificador" => "sec0014"
              "titulo" => "Ago2 pull down"
            ]
            12 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Statistical analysis"
            ]
          ]
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        4 => array:3 [
          "identificador" => "sec0016"
          "titulo" => "Results"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0017"
              "titulo" => "PDGF induces PASMCs abnormal proliferation with concomitantly decreasing let-7b-5p expression in PASMCs"
            ]
            1 => array:2 [
              "identificador" => "sec0018"
              "titulo" => "PDGF-induced abnormal proliferation and migration of PASMCs were antagonized by let-7b-5p mimics&#44; reinforced by let-7b-5p inhibitor"
            ]
            2 => array:2 [
              "identificador" => "sec0019"
              "titulo" => "let-7b-5p directly interacts with IGF1&#44; and down-regulates the expression of IGF1"
            ]
            3 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "IGF1 functions as a target of let-7b-5p on the proliferation and migration of PASMCs"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0021"
          "titulo" => "Discussion"
        ]
        6 => array:2 [
          "identificador" => "sec0022"
          "titulo" => "Authors&#39; contributions"
        ]
        7 => array:2 [
          "identificador" => "sec0023"
          "titulo" => "Funding"
        ]
        8 => array:2 [
          "identificador" => "xack684972"
          "titulo" => "Acknowledgments"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2022-02-16"
    "fechaAceptado" => "2022-05-06"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1682156"
          "palabras" => array:4 [
            0 => "Pulmonary artery smooth muscle cells"
            1 => "let-7b-5p&#44; IGF1"
            2 => "Proliferation"
            3 => "Migration"
          ]
        ]
      ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objectives</span><p id="spara007" class="elsevierStyleSimplePara elsevierViewall">Some previous studies indicated that the excessive proliferation and migration of Pulmonary Artery Smooth Muscle Cells &#40;PASMCs&#41; could be observed in pulmonary artery intima after Pulmonary Embolism &#40;PE&#41; occurred&#46; In addition&#44; recent studies identified some miRNAs that are differentially expressed in the blood of PE patients&#44; which might be used as a diagnostic biomarker for PE&#44; including let-7a-5p&#44; let-7b-5p&#44; and miR-150-5p&#46; Hence&#44; the authors sought to explore the effects of let-7b-5p in PASMC proliferation and migration and the corresponding regulatory mechanism&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara008" class="elsevierStyleSimplePara elsevierViewall">Platelet-Derived Growth Factor &#40;PDGF&#41; was utilized to induce the hyper-proliferation model in PASMCs&#46; The mRNA and protein expression levels were detected by RT-qPCR and western blot&#44; respectively&#46; The proliferation of PASMCs was evaluated by the detection of PCNA expression&#44; as well as CCK-8 and Edu assays&#46; Wound healing and Transwell assays were exploited to assess the migration ability of PASMCs&#46; The targets of let-7b-5p were predicted based on two bioinformatics online tools&#46; Dual-luciferase and Ago2 pull-down assays were applied to confirm the interaction between let-7b-5p and IGF1&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">40&#160;ng&#47;mL PDGF was selected as the optimal concentration to induce PASMCs&#46; let-7b-5p mimics suppressed the proliferation and migration of PDGF-induced PASMCs&#44; while let-7b-5p inhibitor led to the opposite result&#46; In further mechanism exploration&#44; IGF1 was predicted and confirmed as the direct target gene of let-7b-5p&#46; The promotion role of IGF1 overexpression on the proliferation and migration of PDGF-induced PASMCs was dramatically countered by let-7b-5p mimics&#46;</p></span> <span id="abss0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">let-7b-5p prohibits the proliferation and migration of PDGF-induced PASMCs by modulating IGF1&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">PDGF induced the abnormal proliferation of PASMCs and the downregulation of let-7b-5p&#46; &#40;A&#41; The proliferation of PASMCs with different concentrations of PDGF detected by CCK-8 assay&#46; &#40;B&#41; The expression of let-7b-5p in PASMCs with different concentrations of PDGF determined by RT-qPCR&#46; Note&#58; &#42;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">The overexpression of let-7b-5p could antagonize PDGF-induced abnormal proliferation and migration of PASMCs&#46; &#40;A&#41; The transfection efficiency of let-7b-5p mimics and inhibitor verified by RT-qPCR&#46; &#40;B&#41; The PCNA protein expression in PASMCs with different treatments detected by western blot&#46; The proliferation of PASMCs with different treatments detected by &#40;C&#41; CCK-8 and &#40;D&#41; Edu assays &#40;scale bar&#160;&#61;&#160;100&#956;m&#41;&#46; &#40;E&#41; Wound healing and &#40;F&#41; Transwell assays detected the migration ability of PASMCs with different treatments&#59; Scale bar&#160;&#61;&#160;100&#956;m&#46; Note&#58; &#42;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#46;</p>"
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">IGF1 is a direct target of let-7b-5p in PASMCs&#46; &#40;A&#41; Based on the prediction result of starbase&#44; four target genes of let-7b-5p further identified by intersecting functional annotation results&#46; &#40;B&#41; Potential binding sites between IGF1 and let-7b-5p&#46; &#40;C&#41; Dual-luciferase and &#40;D&#41; Ago2 pull down assays indicated the direct interaction between IGF1 and let-7b-5p&#46; &#40;E&#41; The mRNA &#40;left&#41; and protein &#40;right&#41; expression levels of IGF1in PASMCs after transfection with let-7b-5p mimics or inhibitor&#46; Note&#58; &#42;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05 and <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">p</span> &#60; 0&#46;01&#46;</p>"
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          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">let-7b-5p reverses the abnormal proliferation and migration promoted by the IGF1&#46; &#40;A&#41; The protein expression of PCNA and IGF1 in PDGF-induced PASMCs with different transfections detected by western blot&#46; The proliferation of PDGF-induced PASMCs with different treatments detected by &#40;B&#41; CCK-8 and &#40;C&#41; Edu assays &#40;scale bar&#160;&#61;&#160;100&#956;m&#41;&#46; &#40;D&#41; Wound healing and &#40;E&#41; Transwell assay detected the migration ability of PDGF-induced PASMCs with different treatments&#59; Scale bar&#160;&#61;&#160;100&#956;m&#46; Note&#58; &#42;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#46;</p>"
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Article information
ISSN: 18075932
Original language: English
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