Zhou Hongzhong, Zhu Liwen, Zhang Yajun, Chen Lichan, Gou Dong-Mei, Zhang Haohua, Hua Rongmao, Song Jianning, Qiu Chuanghua, Yao Fu-Wen, Wei Xiafei, Gu Dayong, Xu Yong
Department of Laboratory Medicine, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen University, China.
Guangzhou University of Chinese Medicine, Guangzhou, China.
Int J Biol Sci. 2025 Jul 11;21(10):4629-4646. doi: 10.7150/ijbs.111142. eCollection 2025.
Chemotherapy resistance presents a major challenge in the treatment of hepatocellular carcinoma (HCC), with the underlying molecular mechanisms largely unknown. This study aimed to investigate the role of tissue factor pathway inhibitor 2 (TFPI2) in modulating HCC chemosensitivity. We explored the impact of TFPI2 on sorafenib sensitivity in patient-derived organoids and mouse models using immunofluorescence analysis, chromatin immunoprecipitation, and RNA immunoprecipitation. We observed the downregulation of TFPI2 in HCC, and its deletion in mice (TFPI2) accelerated DEN-induced liver tumorigenesis. Notably, TFPI2 overexpression increased sorafenib sensitivity in HCC organoids and models. Mechanistic insights indicated that TFPI2 stabilizes the mRNA of growth arrest and DNA damage-inducible alpha (GADD45A) by engaging the cell cycle and apoptosis regulator 2 (CCAR2), promoting GADD45A-mediated DNA damage and inhibiting homologous recombination repair. Furthermore, TFPI2 protects CCAR2 from ubiquitination-induced degradation by associating with the deubiquitinating enzyme BRCC3. We identified polydatin, a resveratrol glycoside, which upregulates TFPI2 and synergistically enhances the chemosensitizing effect of sorafenib in organoids and . TFPI2 plays a critical role in CCAR2-GADD45A-induced DNA damage repair, providing a strategy to enhance HCC chemosensitivity. Our findings elucidate the molecular intricacies of chemoresistance in HCC and reveal a potential therapeutic target for alleviating this resistance.
化疗耐药性是肝细胞癌（HCC）治疗中的一个主要挑战，其潜在的分子机制 largely unknown。本研究旨在探讨组织因子途径抑制剂2（TFPI2）在调节HCC化疗敏感性中的作用。我们使用免疫荧光分析、染色质免疫沉淀和RNA免疫沉淀，探讨了TFPI2对患者来源的类器官和小鼠模型中索拉非尼敏感性的影响。我们观察到HCC中TFPI2的下调，并且在小鼠中敲除TFPI2（TFPI2-/-）加速了二乙基亚硝胺（DEN）诱导的肝肿瘤发生。值得注意的是，TFPI2过表达增加了HCC类器官和小鼠模型中对索拉非尼的敏感性。机制研究表明，TFPI2通过与细胞周期和凋亡调节因子2（CCAR2）结合来稳定生长停滞和DNA损伤诱导蛋白α（GADD45A）的mRNA，促进GADD45A介导的DNA损伤并抑制同源重组修复。此外，TFPI2通过与去泛素化酶BRCC3结合，保护CCAR2免受泛素化诱导的降解。我们鉴定出白藜芦醇苷虎杖苷，它上调TFPI2并协同增强索拉非尼在类器官和小鼠模型中的化学增敏作用。TFPI2在CCAR2-GADD45A诱导的DNA损伤修复中起关键作用，为增强HCC化疗敏感性提供了一种策略。我们的研究结果阐明了HCC化疗耐药的分子复杂性，并揭示了一种缓解这种耐药性的潜在治疗靶点。
