GPR50 Promotes Hepatocellular Carcinoma Progression via the Notch Signaling Pathway through Direct Interaction with ADAM17

Molecular Therapy: Oncolytics

Hye Yeon Choi¹  Ssang-Goo Cho¹  Kyeongseok Kim¹  Subbroto Kumar Saha¹  Polash Kumar Biswas¹  Geun-Ho Kang¹  Minchan Gil¹  Gwang-Mo Yang¹ 

[1] Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Republic of Korea;

关键词: GPR50;    ADAM17;    ligand-independent Notch signaling;    hepatocellular carcinoma;    HCC progression;    HCC prognosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and it is thus critical to identify novel molecular biomarkers of HCC prognosis and elucidate the molecular mechanisms underlying HCC progression. Here, we show that G-protein-coupled receptor 50 (GPR50) in HCC is overexpressed and that GPR50 knockdown may downregulate cancer cell progression through attenuation of the Notch signaling pathway. GPR50 knockdown was found to reduce HCC progression by inactivating Notch signaling in a ligand-independent manner through a disintegrin and metalloproteinase metallopeptidase domain 17 (ADAM17), a proteolytic enzyme that cleaves the Notch receptor, which was corroborated by GPR50 overexpression in hepatocytes. GPR50 silencing also downregulated transcription and translation of ADAM17 through the AKT/specificity protein-1 (SP1) signaling axis. Notably, GPR50 was found to directly interact with ADAM17. Overall, we demonstrate a novel GPR50-mediated regulation of the ADAM17-Notch signaling pathway, which can provide insights into HCC progression and prognosis and development of Notch-based HCC treatment strategies.

【 授权许可】

Unknown