Clarification on mechanism of carcinogenesis for pediatric congenital biliary dilatation

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: The University of Tokushima
• Principal Investigator: MORI Hiroki 徳島大学, 病院, 特任助教 (70448330)
• Co-Investigator(Kenkyū-buntansha): 矢田 圭吾 徳島大学, 病院, 特任助教 (00633893) ; 石橋 広樹 徳島大学, 大学院医歯薬学研究部(医学域), 講師 (20314867) ; 臼井 規朗 地方独立行政法人大阪府立病院機構大阪母子医療センター(研究所), 小児外科, 診療局長 (30273626) ; 森根 裕二 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (60398021) ; 高橋 章 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (90304047)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 先天性胆道拡張症 / 小児 / 胆道癌 / 発癌 / メタボローム解析

Outline of Final Research Achievements

The purpose was to investigate the mechanism of carcinogenesis for pediatric congenital biliary dilatation (pancreaticobiliary maljunction: PBM) patients using a metabolomics analysis of bile. In the amino acid profiles, 6 potential carcinogenic candidates for PBM were identified; such as leucine, phenylalanine, isoleucine, tyrosine, valine and methionine. In the lipidomic profiles, 11 candidates such as lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylglycerol, triacylglycerol, diacylglycerol, ceramide, sphyngomyeline, fatty acid, hyperforin and vitamin D were identified. The bile metabolites were proved to be extremely similar between PBM and extrahepatic bile duct cancer (EHBC) patients, furthermore, amino acid and lipid metabolism was dramatically altered compared with healthy controls. Therefore, the biliary tract in PBM patients was considered to be always exposed to carcinogenic environments just like that in EHBC patients.

Free Research Field

小児外科

Academic Significance and Societal Importance of the Research Achievements

メタボローム解析を用いた小児先天性胆道拡張症（膵・胆管合流異常）における胆道癌発癌機構の機序解明により、胆汁中の発癌関連候補物質が同定でき、胆道癌患者と同様に胆道がそれらに暴露されていることが分かった。さらに、発癌機序にROS依存的DNA損傷修復応答経路の関与も示唆された。以上のことから、小児期から胆道上皮は発癌ポテンシャルを有している可能性が示唆された。