Li Yanmeng, Ouyang Qin, Chen Zhibin, Zhou Donghu, Li Zhenkun, Yang Xiaoxi, Long Jiang, Chen Guangyong, Li Xiaojin, Jia Siyu, Zi Huaduan, Qi Saiping, Tang Hengcheng, Zhang Bei, Niu Yamei, Xu Anjian, Tong Weimin, Jia Jidong, Huang Jian
Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, 100050, China.
Oncogene. 2025 May;44(19):1323-1335. doi: 10.1038/s41388-025-03301-7. Epub 2025 Feb 19.
Sex disparity is a hepatocellular carcinoma (HCC) hallmark, demonstrating aggressiveness and mortality more frequently in men than in women. However, the components of its basis remain largely unknown. It was identified in HCC frequent loss of heterozygosity of general transcript factor IIH subunit 2 (GTF2H2), a potential estrogen pathway gene. GTF2H2 functions in nucleotide excision repair (NER) and basal transcription, but the function of GTF2H2 in cancer has not been described in depth. Here, it was identified that GTF2H2 inhibited growth and invasive mobility and induced apoptosis of HCC cells, which was up-regulated by estrogen-dependent estrogen receptor alpha (ERα) signaling. Mechanistically, in vitro estrogen-treated HCC models with GTF2H2 knockdown and over-expression showed estrogen-regulated GTF2H2 promoted NER of HCC genomic DNA and inhibited cell cycle progression, and down-regulated PAM/NF-κB pathway. Xenografted HCC mice models showed higher tumor progression of HCC with low GTF2H2 expression in ovariectomized female mice or male mice, but could be rescued by GTF2H2 over-expression, which was also observed in spontaneous tumor mice models. Clinical association analysis of HCC cases showed GTF2H2 expression was higher in female HCC, with correlation positively with ERα expression. Taken together, the estrogen-regulated GTF2H2 may be involved in the development and sex disparity of HCC by maintaining NER-related genomic stability and affecting PAM/NF-κB signaling pathway.
性别差异是肝细胞癌（HCC）的一个特征，男性比女性更频繁地表现出侵袭性和更高的死亡率。然而，其背后的组成因素在很大程度上仍不清楚。在HCC中发现一般转录因子IIH亚基2（GTF2H2）这一潜在雌激素途径基因频繁发生杂合性缺失。GTF2H2在核苷酸切除修复（NER）和基础转录中发挥作用，但GTF2H2在癌症中的功能尚未得到深入描述。在此研究中，发现GTF2H2抑制HCC细胞的生长和侵袭迁移并诱导其凋亡，且其表达受雌激素依赖性雌激素受体α（ERα）信号上调。从机制上讲，在体外雌激素处理的HCC模型中，敲低和过表达GTF2H2显示雌激素调节的GTF2H2促进HCC基因组DNA的NER并抑制细胞周期进程，同时下调PAM/NF-κB途径。异种移植的HCC小鼠模型显示，在去卵巢的雌性小鼠或雄性小鼠中，低GTF2H2表达的HCC肿瘤进展更快，但过表达GTF2H2可使其得到缓解，在自发性肿瘤小鼠模型中也观察到了这一现象。HCC病例的临床关联分析显示，女性HCC中GTF2H2表达更高，且与ERα表达呈正相关。综上所述，雌激素调节的GTF2H2可能通过维持与NER相关的基因组稳定性和影响PAM/NF-κB信号通路参与HCC的发生发展及性别差异。
