Loss of phospholipase C gamma 1 suppresses hepatocellular carcinogenesis through blockade of STAT3-mediated cancer development

Abstract

Phospholipase C gamma 1 (PLC gamma 1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of PLC gamma 1 on tumors, the pathogenic role of PLC gamma 1 in the tumorigenesis and development of hepatocellular carcinoma (HCC) remains unknown. To investigate the function of PLC gamma 1 in HCC, we generated hepatocyte-specific PLC gamma 1 conditional knockout (PLC gamma 1(f/f); Alb-Cre) mice and induced HCC with diethylnitrosamine (DEN). Here, we identified that hepatocyte-specific PLC gamma 1 deletion effectively prevented DEN-induced HCC in mice. PLC gamma 1(f/f); Alb-Cre mice showed reduced tumor burden and tumor progression, as well as a decreased incidence of HCC and less marked proliferative and inflammatory responses. We also showed that oncogenic phenotypes such as repressed apoptosis, and promoted proliferation, cell cycle progression and migration, were induced by PLC gamma 1. In terms of molecular mechanism, PLC gamma 1 regulated the activation of signal transducer and activator of transcription 3 (STAT3) signaling. Moreover, PLC gamma 1 expression is elevated in human HCC and correlates with a poor prognosis in patients with HCC. Our results suggest that PLC gamma 1 promotes the pathogenic progression of HCC, and PLC gamma 1/STAT3 axis was identified as a potential therapeutic target pathway for HCC.