Estrogen-related receptor γ is upregulated in liver cancer and its inhibition suppresses liver cancer cell proliferation via induction of p21 and p27

Orphan nuclear receptor estrogen-related receptor gamma (ERR gamma) regulates cell growth and tumorigenesis in various cancers. However, the clinical relevance of ERR gamma to hepatocellular carcinoma (HCC) remains unclear. Here we examined the clinical significance of ERR gamma in HCC and its potential as a therapeutic target. ERR gamma levels in tissues from completely resected specimens from 190 HCC patients were examined immunohistochemically and their association with clinical stage and pathological grade was analyzed. Small interfering RNA (siRNA)-mediated knockdown of ERR gamma (siRNA-ERR gamma) or an ERR gamma inverse agonist, GSK5182, were also used to examine the effects of ERR gamma inhibition on the proliferation and growth of a human hepatoma cell line, PLC/PRF/5. Immunohistochemical analysis revealed that tumor tissues showed higher levels of ERR gamma-positivity than adjacent non-tumor lesions. Tumors showing high levels of ERR gamma immunoreactivity also had advanced tumor node metastasis (TNM) and Barcelona Clinic Liver Cancer stages and a higher Edmondson-Steiner grade. In addition, high-level expression of ERR gamma in tumors of advanced TNM stage correlated with poorer overall survival. Treatment of PLC/PRF/5 cells with siRNA-ERR gamma or GSK5182 inhibited proliferation through G1 arrest, increased expression of p21 and p27 and decreased expression of phosphorylated retinoblastoma protein. GSK5182-induced reactive oxygen species also suppressed the proliferation of PLC/PRF/5 cells. The present study showed that ERR gamma expression is clinically significant in HCC; therefore, it can be considered a biomarker for HCC diagnosis. Moreover, the results provide a rationale for the use of ERR gamma inhibitors such as GSK5182 as potential therapeutic agents.