Molecular mechanisms of HCG18 in the sorafenib resistance of hepatocellular carcinoma
Molecular mechanisms of HCG18 in the sorafenib resistance of hepatocellular carcinoma
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DOI：
10.1097/cad.0000000000001539
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发表时间：
2023-09
影响因子：
2.3
通讯作者：
Heping Li;Jie Hu;Lijie Qiu;Yijiang Wu;Baiyin Zhong;Rong Ye;B. Xie
中科院分区：
文献类型：
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作者：
Heping Li;Jie Hu;Lijie Qiu;Yijiang Wu;Baiyin Zhong;Rong Ye;B. Xie
索拉非尼已被批准用于治疗晚期肝细胞癌（HCC），但经常发生耐药。因此，阐明索拉非尼耐药的机制，寻找克服索拉非尼耐药的有效策略具有重要意义。采用qPCR、MTT、克隆形成、流式细胞术和TUNEL法检测HCG 18的表达，探讨HCG 18在肝癌索拉非尼耐药中的作用。采用RNA pull-down、RNA免疫沉淀、免疫荧光标记、荧光素酶报告基因分析、western blot和qPCR等方法研究HCG 18调节肝癌索拉非尼耐药的机制。我们的研究结果表明，HCC中HCG 18显著升高，这导致HCC患者的5年生存期缩短。索拉非尼可诱导HCG 18的表达，提示HCG 18可能参与了肝癌索拉非尼耐药的发生。进一步的分析表明，HCG 18的敲低可以降低HCC细胞的存活率并增加细胞凋亡。HCG 18通过与USP 15结合，调节p65、TAB 2和TAB 3的蛋白稳定性，进而调节p65的核定位，最终调节NF-κB信号通路。我们的研究结果表明，HCG 18在肝癌索拉非尼耐药中起重要作用。HCG 18基因的敲低可提高肝癌细胞对索拉非尼的敏感性，提示以HCG 18为靶点可能是克服肝癌索拉非尼耐药的有效策略。
Sorafenib has been approved for advance hepatocellular carcinoma (HCC), however, drug resistance often occurred. Therefore, it is of great significance to clarify the underlying mechanisms of sorafenib resistance and to find out the effective strategies to overcome sorafenib resistance. The expression of HCG18 was detected by qPCR, MTT, colony formation, flow cytometry and TUNEL assay were used to explore the function of HCG18 on sorafenib resistance in HCC. RNA pull-down, RNA immunoprecipitation, immunofluorescence labeling, luciferase reporter assay, western blot and qPCR were used to investigate the mechanism of HCG18 regulating sorafenib resistance in HCC. Our results showed that HCG18 was significantly increased in HCC, which resulted in shorter 5-year survival for patients with HCC. Sorafenib can induce the expression of HCG18, suggesting HCG18 might be involved in sorafenib resistance in HCC. Further analysis showed that knockdown of HCG18 can reduce viability and increase apoptosis of HCC cells. Mechanistically, HCG18 can bind to USP15, further regulated the protein stability of p65, TAB2 and TAB3, and nuclear location of p65, which finally modulated the NF-κB signaling. Our findings showed that HCG18 played an important role in sorafenib resistance in HCC. And knockdown of HCG18 can promote the sensitivity of HCC cells to sorafenib, inferring that targeting HCG18 might be an effective strategy to overcome sorafenib resistance in HCC.