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MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis

BACKGROUND: 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 apoptos...

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Autores principales: Otsubo, Takeshi, Akiyama, Yoshimitsu, Hashimoto, Yutaka, Shimada, Shu, Goto, Kentaro, Yuasa, Yasuhito
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029394/
https://www.ncbi.nlm.nih.gov/pubmed/21304604
http://dx.doi.org/10.1371/journal.pone.0016617
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author Otsubo, Takeshi
Akiyama, Yoshimitsu
Hashimoto, Yutaka
Shimada, Shu
Goto, Kentaro
Yuasa, Yasuhito
author_facet Otsubo, Takeshi
Akiyama, Yoshimitsu
Hashimoto, Yutaka
Shimada, Shu
Goto, Kentaro
Yuasa, Yasuhito
author_sort Otsubo, Takeshi
collection PubMed
description BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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.
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spelling pubmed-30293942011-02-08 MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis Otsubo, Takeshi Akiyama, Yoshimitsu Hashimoto, Yutaka Shimada, Shu Goto, Kentaro Yuasa, Yasuhito PLoS One Research Article BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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. Public Library of Science 2011-01-27 /pmc/articles/PMC3029394/ /pubmed/21304604 http://dx.doi.org/10.1371/journal.pone.0016617 Text en Otsubo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Otsubo, Takeshi
Akiyama, Yoshimitsu
Hashimoto, Yutaka
Shimada, Shu
Goto, Kentaro
Yuasa, Yasuhito
MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis
title MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis
title_full MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis
title_fullStr MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis
title_full_unstemmed MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis
title_short MicroRNA-126 Inhibits SOX2 Expression and Contributes to Gastric Carcinogenesis
title_sort microrna-126 inhibits sox2 expression and contributes to gastric carcinogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029394/
https://www.ncbi.nlm.nih.gov/pubmed/21304604
http://dx.doi.org/10.1371/journal.pone.0016617
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