Lin Wei, Zhao Zhiguang, Du Wenjun, Ni Zhonglin, Pan Chenwei, Fang Peipei, Li Jie, ZhuGe Lu, Jin Shuanghong
Department of Infectious Diseases, The Second Affiliated Hospital of Wenzhou Medical University, #1111 of Wenzhou Wenzhou Avenue, Longwan District, Wenzhou, Zhejiang, China.
Department of Pathology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Dig Dis Sci. 2024 Feb;69(2):491-501. doi: 10.1007/s10620-023-08175-x. Epub 2024 Jan 3.
Previous reports have suggested IFI16 as a tumor suppressor in hepatocellular carcinoma (HC). Nonetheless, the biological significance of IFI16 and its mechanism concerning resistance to cisplatin (DDP) in HC requires further exploration.
Samples of tumor and corresponding para-carcinoma tissues were acquired from patients with HC. Furthermore, DDP-resistant cell lines of HC, specifically HCC, Huh7 and Hepatoblastoma, HepG3, were generated by gradually increasing the concentration of DDP. Cell apoptosis and DNA damage were evaluated by utilizing flow cytometry assay and TUNEL staining. The interaction between IFI16 and interferon regulatory factor 3 (IRF3) proteins were analyzed using Co-Immunoprecipitation (Co-IP) assay. In vivo assays were conducted by establishing HC subcutaneous xenograft tumor models.
The study found a reduction in IFI16 expression in both HC tissues and DDP-resistant HC cell lines. The binding of IFI16 to IRF3 regulated DNA damage-associated markers in vitro. Overexpression of IFI16 heightened the susceptibility of DDP-induced apoptosis and DNA damage, which was counteracted by IRF3 knockdown, while strengthened by IRF3 overexpression. Moreover, overexpression of IFI16 diminished in vivo DDP-resistant HC tumorigenicity.
In summary, our findings suggest that IFI16 serves as a tumor suppressor in HC by promoting DNA damage via its interaction with IRF3, thereby reversing DDP resistance.
既往报道提示IFI16在肝细胞癌（HC）中作为一种肿瘤抑制因子。尽管如此，IFI16的生物学意义及其在HC中对顺铂（DDP）耐药的机制仍需进一步探索。
从HC患者获取肿瘤及相应癌旁组织样本。此外，通过逐步提高DDP浓度建立HC的DDP耐药细胞系，具体为肝癌细胞系HCC、Huh7以及肝母细胞瘤细胞系HepG3。利用流式细胞术检测和TUNEL染色评估细胞凋亡和DNA损伤。采用免疫共沉淀（Co-IP）检测分析IFI16与干扰素调节因子3（IRF3）蛋白之间的相互作用。通过建立HC皮下异种移植肿瘤模型进行体内实验。
研究发现HC组织和DDP耐药HC细胞系中IFI16表达均降低。体外实验中IFI16与IRF3的结合调节了DNA损伤相关标志物。IFI16过表达增强了DDP诱导的细胞凋亡和DNA损伤的易感性，IRF3敲低可抵消这种作用，而IRF3过表达则增强这种作用。此外，IFI16过表达降低了体内DDP耐药HC的致瘤性。
总之，我们的研究结果表明，IFI16在HC中作为肿瘤抑制因子，通过与IRF3相互作用促进DNA损伤，从而逆转DDP耐药。
