KMID : 0620920160480030009
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Experimental & Molecular Medicine 2016 Volume.48 No. 3 p.9 ~ p.9
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Estrogen-related receptor ¥ã is upregulated in liver cancer and its inhibition suppresses liver cancer cell proliferation via induction of p21 and p27
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Kim Ji-Hyun
Choi Yeon-Kyung Byun Jun-Kyu Kim Mi-Kyung Kang Yu-Na Kim Seong-Heon Lee Sung-Woo Jang Byoung-Kuk Park Keun-Gyu
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Abstract
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Orphan nuclear receptor estrogen-related receptor ¥ã (ERR¥ã) regulates cell growth and tumorigenesis in various cancers. However, the clinical relevance of ERR¥ã to hepatocellular carcinoma (HCC) remains unclear. Here we examined the clinical significance of ERR¥ã in HCC and its potential as a therapeutic target. ERR¥ã 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¥ã (siRNA-ERR¥ã) or an ERR¥ã inverse agonist, GSK5182, were also used to examine the effects of ERR¥ã 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¥ã-positivity than adjacent non-tumor lesions. Tumors showing high levels of ERR¥ã 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¥ã in tumors of advanced TNM stage correlated with poorer overall survival. Treatment of PLC/PRF/5 cells with siRNA-ERR¥ã 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¥ã 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¥ã inhibitors such as GSK5182 as potential therapeutic agents.
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KEYWORD
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