Clinicopathological Study of YAP1 Expression in High-Grade Neuroendocrine Carcinoma of the Lung

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15418
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Matsuoka Ryota 筑波大学, 医学医療系, 講師 (70833804)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 神経内分泌癌 / 大細胞型神経内分泌癌 / 小細胞癌 / ASCL1 / NEUROD1 / POU2F3 / YAP1 / HNF4α

Outline of Final Research Achievements

We conducted immunohistochemistry using specimens of small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) resected at our institution to analyze the heterogeneity of various factors (ASCL1, NEUROD1, POU2F3, YAP1) that define subtypes. During this analysis, we discovered a group expressing HNF4α, a gastrointestinal marker. Compared to the group that did not express HNF4α, this group had significantly poorer prognosis. Furthermore, it was found that they specifically possessed mutations in the NFE2L2/KEAP1 genes. Additionally, experiments using cell lines demonstrated that HNF4α promotes cell proliferation in neuroendocrine carcinomas by inhibiting apoptosis.

Free Research Field

人体病理

Academic Significance and Societal Importance of the Research Achievements

SCLCとLCNECは、高悪性度神経内分泌癌 (HGNEC)に分類され、侵攻性が高く予後不良である。有効な薬剤も限られておりたな治療法の創出が必要である。本研究ではHGNEC内にHNF4αを発現する新たなグループを発見しHNF4α発現は悪性度に関連している可能性を示した。HNF4α発現HGNECはHGNEC内でも特殊なプロファイルおよび生物学的挙動を有しており、従来とは異なった治療の効果が予想される。今後はHNF4α発現HGNECの特性を解析することで、HNF4αの発現に立脚したHGNECの新たなサブタイプ分類と、それに合わせた最適な治療法の創出を目指す。