Functional analysis of miR-375, a candidate of tumor suppressor miRNA in gastric cancer

2011 Fiscal Year Final Research Report

• Project/Area Number: 22790349
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Human pathology
• Research Institution: Oita University
• Principal Investigator: TSUKAMOTO Yoshiyuki 大分大学, 医学部, 助教 (00433053)
• Project Period (FY): 2010 – 2011
• Keywords: マイクロRNA / 胃癌

Research Abstract

In this study, we found that miRNA-375(miR-375) was the most downregulated and that its ectopic expression in gastric carcinoma cells markedly reduced cell viability via the caspase-mediated apoptosis pathway. Interestingly, we found that expression of miR-375 inhibited expression of PDK1, which is a direct target of miR-375, followed by suppression of Akt phosphorylation. Further analysis by gene expression microarray revealed that 14-3-3zeta, a potent antiapoptotic gene, was significantly downregulated at both the mRNA and protein levels in cells transfected with miR-375. The activity of a luciferase reporter containing the miR-375 binding sequence at the 3' untranslated region(UTR) of 14-3-3zeta mRNA was repressed by the ectopic expression of miR-375, suggesting that miR-375 targets the 3' UTR of 14-3-3zeta. In addition, knockdown of either PDK1 or 14-3-3zeta in gastric carcinoma cells induced caspase activation, which was also observed in miR-375-transfected cells, suggesting that miR-375 may exert its proapoptotic function, at least in part, through the downregulation of PDK1 and 14-3-3zeta. Taken together, we propose that miR-375 is a candidate tumor suppressor miRNA in gastric carcinoma

Research Products

• [Journal Article] Genomic profiling of submucosal-invasive gastric cancer by array-based comparative genomic hybridization (2011)
  • Author(s): Kuroda A, Tsukamoto Y, Nguyen LT, Noguchi T, Takeuchi I, Uchida M, Uchida T, Hijiya N, Nakada C, Okimoto T, Kodama M, Murakami K, Matsuura K, Seto M, Ito H, Fujioka T, Moriyama M
  • Journal Title: PLoS One Volume: 6(7) Pages: e22313
• [Journal Article] Overexpression of miR-210, a downstream target of HIF1α, causes centrosome amplification in renal carcinoma cells (2011)
  • Author(s): Nakada C, Tsukamoto Y, Matsuura K, Nguyen TL, Hijiya N, Uchida T, Sato F, Mimata H, Seto M, Moriyama M
  • Journal Title: J Pathol Volume: 224(2) Pages: 280-8
• [Journal Article] MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta (2010)
  • Author(s): Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T, Hijiya N, Matsuura K, Fujioka T, Seto M, Moriyama M
  • Journal Title: Cancer Res Volume: 70(6) Pages: 2339-49
• [Presentation] 胃癌におけるマイクロRNA発現 (2011)
  • Author(s): 塚本善之
  • Organizer: 第100回日本病理学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-04-28
• [Remarks]
  • URL: http://www.med.oita-u.ac.jp/byori2/