Identification of miRNAs involved in the premalignant lesions in gastrointestinal tract and their malignant transformation

Research Project

Project/Area Number	19K17483
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 53010:Gastroenterology-related
Research Institution	The University of Tokyo
Principal Investigator	Takeuchi Chihiro 東京大学, 医学部附属病院, 届出研究員 (60836055)
Project Period (FY)	2019-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Keywords	miRNA / 網羅的遺伝子発現解析 / 非乳頭部十二指腸上皮性腫瘍 / Wnt/βcatenin pathway / APC mutation / 十二指腸腫瘍 / 遺伝子発現解析 / microarray / 癌 / 発現・制御 / 内科
Outline of Research at the Start	本研究は胃・大腸・十二指腸の前癌病変を含む早期腫瘍検体を用いて高精度のRNA・DNAを抽出し、網羅的遺伝子発現解析を行う。腫瘍で特異的に発現しているmiRNAについて、前癌病変及び癌の特異的マーカーとなるmiRNAを明らかにし、targetとなる遺伝子を同定するとともに、病理学的な悪性度予測マーカーの確立とin vitro・in vivoの系でのmiRNA⇔mRNAのinteraction消化管上皮性腫瘍の発症機序解明を行う。またゲノムシークエンスから得られた遺伝子変異とmiRNA発現異常の機序解明を行う。
Outline of Final Research Achievements	We performed comprehensive gene expression analysis of miRNA / mRNA using nonpapillary duodenal epithelial tumors. Gene ontology analysis showed that the expression of the target genes of miR-135b, which was significantly expressed in tumors, was decreased, and that it was associated with the APC gene and Wnt pathway. Indeed, immunostaining using resected specimens showed high expression level of miR-135b and abnormal accumulation of β-catenin. And APC gene mutation was rarely observed in the tumors. The induction of miR-135b expression decreased the expression of APC protein. These results suggested that upregulation of miR-135b may inhibit APC protein expression, leading tumorigenesis through upregulation of Wnt pathway signaling in nonpapillary duodenal epithelial tumors.
Academic Significance and Societal Importance of the Research Achievements	十二指腸上皮性腫瘍の前癌病変と早期癌におけるmiRNAの発現異常とその腫瘍発症機序のメカニズムについて比較検討した報告は少ない。本研究では網羅的遺伝子発現解析と病理学的検討及び基礎的検討を通してmiRNAによる腫瘍発症のメカニズムを明らかにした。消化管において前癌病変・早期癌の初期発症に関与する分子メカニズムを解明する事は、有効な診断法・治療法の確立や化学療法予測を可能にするという点で臨床的意義が大きいと考えられる。