Pancreatic stellate cells are activated by vitamin A deficiency, causing fibrosis and malignant transformation in pancreatic cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16588
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Ono Yusuke 札幌医科大学, 医学部, 助教 (90812355)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 膵がん / レチノイン酸 / ビタミンA / レチノイン酸代謝酵素

Outline of Final Research Achievements

We performed an immunohistochemical study of CYP26A1 using pancreatic cancer surgical material. CYP26A1 was expressed predominantly in adenocarcinoma cells, but not in fibroblasts of the stroma. Its expression varied from negative to highly positive. We measured staining intensity at each differentiation level of pancreatic carcinoma. We found a significant association between expression status and differentiation level in adenocarcinoma.
Next, we generated and analyzed CYP26A1 knockout cell lines using the CISPR-Cas9 system. Defective expression of CYP26A1 suppressed proliferative and migratory ability upon retinoic acid treatment. These results suggest that CYP26A1 is highly expressed in some pancreatic cancer tissues and is involved in malignant transformation by inactivating retinoic acid.

Free Research Field

人体病理学

Academic Significance and Societal Importance of the Research Achievements

CYP26A1は今回の検討で主に癌細胞に発現しており、細胞株の検討で癌悪性化に関わることが示唆された。これは、癌細胞ではCYP26A1の発現によってレチノイン酸に対する感受性が低下しており、レチノイン酸の投与もしくはCYP26A1を標的とした治療につながる可能性のある結果である。また、癌組織中では、癌細胞に発現したCYP26A1が組織環境中のビタミンA欠乏を招き、星細胞を活性化して線維化の形成機序の一部を担っていることも考えられる。これらの新規の治療標的、戦略や病態理解は膵癌の極めて悪い予後を改善する可能性を秘めている。