MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis
SRY (sex-determining region Y)-box 2 (SOX2) is a crucial transcription factor for the maintenance of embryonic stem cell pluripotency and the determination of cell fate. Previously, we demonstrated that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis, and that...
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| description | SRY (sex-determining region Y)-box 2 (SOX2) is a crucial transcription factor for the maintenance of embryonic stem cell pluripotency and the determination of cell fate. Previously, we demonstrated that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis, and that SOX2 expression is frequently down-regulated in gastric cancers. However, the mechanisms underlying loss of SOX2 expression and its target genes involved in gastric carcinogenesis remain largely unknown. Here, we assessed whether microRNAs (miRNAs) regulate SOX2 expression in gastric cancers. Furthermore, we attempted to find downstream target genes of SOX2 contributing to gastric carcinogenesis.
We performed in silico analysis and focused on miRNA-126 (miR-126) as a potential SOX2 regulator. Gain- and loss-of function experiments and luciferase assays revealed that miR-126 inhibited SOX2 expression by targeting two binding sites in the 3'-untranslated region (3'-UTR) of SOX2 mRNA in multiple cell lines. In addition, miR-126 was highly expressed in some cultured and primary gastric cancer cells with low SOX2 protein levels. Furthermore, exogenous miR-126 over-expression as well as siRNA-mediated knockdown of SOX2 significantly enhanced the anchorage-dependent and -independent growth of gastric cancer cell lines. We next performed microarray analysis after SOX2 over-expression in a gastric cancer cell line, and found that expression of the placenta-specific 1 (PLAC1) gene was significantly down-regulated by SOX2 over-expression. siRNA- and miR-126-mediated SOX2 knockdown experiments revealed that miR-126 positively regulated PLAC1 expression through suppression of SOX2 expression in gastric cancer cells.
Taken together, our results indicate that miR-126 is a novel miRNA that targets SOX2, and PLAC1 may be a novel downstream target gene of SOX2 in gastric cancer cells. These findings suggest that aberrant over-expression of miR-126 and consequent SOX2 down-regulation may contribute to gastric carcinogenesis. |
| doi_str_mv | 10.1371/journal.pone.0016617 |
| format | Article |
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We performed in silico analysis and focused on miRNA-126 (miR-126) as a potential SOX2 regulator. Gain- and loss-of function experiments and luciferase assays revealed that miR-126 inhibited SOX2 expression by targeting two binding sites in the 3'-untranslated region (3'-UTR) of SOX2 mRNA in multiple cell lines. In addition, miR-126 was highly expressed in some cultured and primary gastric cancer cells with low SOX2 protein levels. Furthermore, exogenous miR-126 over-expression as well as siRNA-mediated knockdown of SOX2 significantly enhanced the anchorage-dependent and -independent growth of gastric cancer cell lines. We next performed microarray analysis after SOX2 over-expression in a gastric cancer cell line, and found that expression of the placenta-specific 1 (PLAC1) gene was significantly down-regulated by SOX2 over-expression. siRNA- and miR-126-mediated SOX2 knockdown experiments revealed that miR-126 positively regulated PLAC1 expression through suppression of SOX2 expression in gastric cancer cells.
Taken together, our results indicate that miR-126 is a novel miRNA that targets SOX2, and PLAC1 may be a novel downstream target gene of SOX2 in gastric cancer cells. These findings suggest that aberrant over-expression of miR-126 and consequent SOX2 down-regulation may contribute to gastric carcinogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0016617</identifier><identifier>PMID: 21304604</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3' Untranslated Regions ; Aberration ; Analysis ; Apoptosis ; Binding Sites ; Biology ; Biotechnology ; Cancer ; Carcinogenesis ; Carcinogens ; Cell cycle ; Cell fate ; Cell Line, Tumor ; Cell Transformation, Neoplastic - genetics ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA microarrays ; Embryonic stem cells ; Female ; Gastric cancer ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Growth factors ; Humans ; Leukemia ; Luciferase ; Medicine ; MicroRNA ; MicroRNAs ; MicroRNAs - physiology ; miRNA ; Oncology ; Overexpression ; Placenta ; Pluripotency ; Pregnancy Proteins - genetics ; Proteins ; Ribonucleic acid ; RNA ; siRNA ; Sox2 protein ; SOXB1 Transcription Factors - antagonists & inhibitors ; SOXB1 Transcription Factors - genetics ; Stem cells ; Stomach cancer ; Stomach Neoplasms - etiology ; Stomach Neoplasms - genetics ; Transcription factors ; Tumor cell lines</subject><ispartof>PloS one, 2011-01, Vol.6 (1), p.e16617</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Otsubo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Otsubo et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c790t-afb4af638679e49129b03f475ad5c372930938af6c18728f42d21062863b8d9d3</citedby><cites>FETCH-LOGICAL-c790t-afb4af638679e49129b03f475ad5c372930938af6c18728f42d21062863b8d9d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029394/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029394/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21304604$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Dalmasso, Guillaume</contributor><creatorcontrib>Otsubo, Takeshi</creatorcontrib><creatorcontrib>Akiyama, Yoshimitsu</creatorcontrib><creatorcontrib>Hashimoto, Yutaka</creatorcontrib><creatorcontrib>Shimada, Shu</creatorcontrib><creatorcontrib>Goto, Kentaro</creatorcontrib><creatorcontrib>Yuasa, Yasuhito</creatorcontrib><title>MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>SRY (sex-determining region Y)-box 2 (SOX2) is a crucial transcription factor for the maintenance of embryonic stem cell pluripotency and the determination of cell fate. Previously, we demonstrated that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis, and that SOX2 expression is frequently down-regulated in gastric cancers. However, the mechanisms underlying loss of SOX2 expression and its target genes involved in gastric carcinogenesis remain largely unknown. Here, we assessed whether microRNAs (miRNAs) regulate SOX2 expression in gastric cancers. Furthermore, we attempted to find downstream target genes of SOX2 contributing to gastric carcinogenesis.
We performed in silico analysis and focused on miRNA-126 (miR-126) as a potential SOX2 regulator. Gain- and loss-of function experiments and luciferase assays revealed that miR-126 inhibited SOX2 expression by targeting two binding sites in the 3'-untranslated region (3'-UTR) of SOX2 mRNA in multiple cell lines. In addition, miR-126 was highly expressed in some cultured and primary gastric cancer cells with low SOX2 protein levels. Furthermore, exogenous miR-126 over-expression as well as siRNA-mediated knockdown of SOX2 significantly enhanced the anchorage-dependent and -independent growth of gastric cancer cell lines. We next performed microarray analysis after SOX2 over-expression in a gastric cancer cell line, and found that expression of the placenta-specific 1 (PLAC1) gene was significantly down-regulated by SOX2 over-expression. siRNA- and miR-126-mediated SOX2 knockdown experiments revealed that miR-126 positively regulated PLAC1 expression through suppression of SOX2 expression in gastric cancer cells.
Taken together, our results indicate that miR-126 is a novel miRNA that targets SOX2, and PLAC1 may be a novel downstream target gene of SOX2 in gastric cancer cells. These findings suggest that aberrant over-expression of miR-126 and consequent SOX2 down-regulation may contribute to gastric carcinogenesis.</description><subject>3' Untranslated Regions</subject><subject>Aberration</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Binding Sites</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Cell cycle</subject><subject>Cell fate</subject><subject>Cell Line, Tumor</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA microarrays</subject><subject>Embryonic stem cells</subject><subject>Female</subject><subject>Gastric cancer</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Luciferase</subject><subject>Medicine</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - physiology</subject><subject>miRNA</subject><subject>Oncology</subject><subject>Overexpression</subject><subject>Placenta</subject><subject>Pluripotency</subject><subject>Pregnancy Proteins - genetics</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>siRNA</subject><subject>Sox2 protein</subject><subject>SOXB1 Transcription Factors - antagonists & inhibitors</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>Stem cells</subject><subject>Stomach cancer</subject><subject>Stomach Neoplasms - etiology</subject><subject>Stomach Neoplasms - genetics</subject><subject>Transcription factors</subject><subject>Tumor cell lines</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1v0zAUhiMEYqPwDxBEQkJw0eKv2PENUjXxUWlQaQPEnXXiOKmn1O7sBI1_j0uzqUG7QL7w13NeH5_zZtlzjBaYCvzuyg_BQbfYeWcWCGHOsXiQnWJJyZwTRB8erU-yJzFeIVTQkvPH2QnBFDGO2Gm2_mJ18Bdfl3NMeG7dxla2j_nl-ifJzc0umBitdzm4Otfe9cFWQ29i3vu8hZi2OtcQtHW-Nc5EG59mjxroonk2zrPs-8cP384-z8_Xn1Zny_O5FhL1c2gqBg1P6QhpmMREVog2TBRQF5oKIimStEyExqUgZcNITTDipOS0KmtZ01n28qC763xUYy2iSkJMIsmSwCxbHYjaw5XaBbuF8Ft5sOrvgQ-tgtBb3RlVIaCiaphkCFhZgARKsICC01oClzppvR9fG6qtqbVJlYBuIjq9cXajWv9LUZQykSwJvBkFgr8eTOzV1kZtug6c8UPKm_GSFpiUOKGv_kHv_91ItZA-YF3j07t6L6qWTHCJuCj2Wot7qDRqs7Wpn6ax6XwS8HYSsO-5uelbGGJUq8uL_2fXP6bs6yN2Y6DrN9F3Q5_MFacgO4DJlTEG09wVGSO19_1tNdTe92r0fQp7cdygu6Bbo9M_7vn64g</recordid><startdate>20110127</startdate><enddate>20110127</enddate><creator>Otsubo, Takeshi</creator><creator>Akiyama, Yoshimitsu</creator><creator>Hashimoto, Yutaka</creator><creator>Shimada, Shu</creator><creator>Goto, Kentaro</creator><creator>Yuasa, Yasuhito</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110127</creationdate><title>MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis</title><author>Otsubo, Takeshi ; Akiyama, Yoshimitsu ; Hashimoto, Yutaka ; Shimada, Shu ; Goto, Kentaro ; Yuasa, Yasuhito</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c790t-afb4af638679e49129b03f475ad5c372930938af6c18728f42d21062863b8d9d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>3' Untranslated Regions</topic><topic>Aberration</topic><topic>Analysis</topic><topic>Apoptosis</topic><topic>Binding Sites</topic><topic>Biology</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Carcinogenesis</topic><topic>Carcinogens</topic><topic>Cell cycle</topic><topic>Cell fate</topic><topic>Cell Line, Tumor</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA microarrays</topic><topic>Embryonic stem cells</topic><topic>Female</topic><topic>Gastric cancer</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Luciferase</topic><topic>Medicine</topic><topic>MicroRNA</topic><topic>MicroRNAs</topic><topic>MicroRNAs - physiology</topic><topic>miRNA</topic><topic>Oncology</topic><topic>Overexpression</topic><topic>Placenta</topic><topic>Pluripotency</topic><topic>Pregnancy Proteins - genetics</topic><topic>Proteins</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>siRNA</topic><topic>Sox2 protein</topic><topic>SOXB1 Transcription Factors - antagonists & inhibitors</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>Stem cells</topic><topic>Stomach cancer</topic><topic>Stomach Neoplasms - 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Previously, we demonstrated that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis, and that SOX2 expression is frequently down-regulated in gastric cancers. However, the mechanisms underlying loss of SOX2 expression and its target genes involved in gastric carcinogenesis remain largely unknown. Here, we assessed whether microRNAs (miRNAs) regulate SOX2 expression in gastric cancers. Furthermore, we attempted to find downstream target genes of SOX2 contributing to gastric carcinogenesis.
We performed in silico analysis and focused on miRNA-126 (miR-126) as a potential SOX2 regulator. Gain- and loss-of function experiments and luciferase assays revealed that miR-126 inhibited SOX2 expression by targeting two binding sites in the 3'-untranslated region (3'-UTR) of SOX2 mRNA in multiple cell lines. In addition, miR-126 was highly expressed in some cultured and primary gastric cancer cells with low SOX2 protein levels. Furthermore, exogenous miR-126 over-expression as well as siRNA-mediated knockdown of SOX2 significantly enhanced the anchorage-dependent and -independent growth of gastric cancer cell lines. We next performed microarray analysis after SOX2 over-expression in a gastric cancer cell line, and found that expression of the placenta-specific 1 (PLAC1) gene was significantly down-regulated by SOX2 over-expression. siRNA- and miR-126-mediated SOX2 knockdown experiments revealed that miR-126 positively regulated PLAC1 expression through suppression of SOX2 expression in gastric cancer cells.
Taken together, our results indicate that miR-126 is a novel miRNA that targets SOX2, and PLAC1 may be a novel downstream target gene of SOX2 in gastric cancer cells. These findings suggest that aberrant over-expression of miR-126 and consequent SOX2 down-regulation may contribute to gastric carcinogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21304604</pmid><doi>10.1371/journal.pone.0016617</doi><tpages>e16617</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3' Untranslated Regions Aberration Analysis Apoptosis Binding Sites Biology Biotechnology Cancer Carcinogenesis Carcinogens Cell cycle Cell fate Cell Line, Tumor Cell Transformation, Neoplastic - genetics Deoxyribonucleic acid DNA DNA methylation DNA microarrays Embryonic stem cells Female Gastric cancer Gene expression Gene Expression Regulation, Neoplastic Genes Growth factors Humans Leukemia Luciferase Medicine MicroRNA MicroRNAs MicroRNAs - physiology miRNA Oncology Overexpression Placenta Pluripotency Pregnancy Proteins - genetics Proteins Ribonucleic acid RNA siRNA Sox2 protein SOXB1 Transcription Factors - antagonists & inhibitors SOXB1 Transcription Factors - genetics Stem cells Stomach cancer Stomach Neoplasms - etiology Stomach Neoplasms - genetics Transcription factors Tumor cell lines |
| title | MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T03%3A51%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MicroRNA-126%20inhibits%20SOX2%20expression%20and%20contributes%20to%20gastric%20carcinogenesis&rft.jtitle=PloS%20one&rft.au=Otsubo,%20Takeshi&rft.date=2011-01-27&rft.volume=6&rft.issue=1&rft.spage=e16617&rft.pages=e16617-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0016617&rft_dat=%3Cgale_plos_%3EA476906751%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1294909429&rft_id=info:pmid/21304604&rft_galeid=A476906751&rft_doaj_id=oai_doaj_org_article_b0a37bf4940a485a9a3217a563d9a69c&rfr_iscdi=true |