TRAF2 inhibits senescence in hepatocellular carcinoma cells via regulating the ROMO1/ NAD+/SIRT3/SOD2 axis
TRAF2 inhibits senescence in hepatocellular carcinoma cells via regulating the ROMO1/ NAD+/SIRT3/SOD2 axis
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DOI：
10.1016/j.freeradbiomed.2023.11.035
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发表时间：
2023-12-15
影响因子：
7.4
通讯作者：
Zheng，Min
中科院分区：
文献类型：
--
作者：
Yao，Jiping;Liang，Xue;Zheng，Min
通过细胞衰老抑制肿瘤的增殖已成为一种很有前途的抗肿瘤治疗方法。肿瘤坏死因子受体相关因子2(TRAF2)是一种参与NF-κB信号通路和ROS产生的接头蛋白，与肝细胞癌的增殖密切相关。然而，目前对TRAF2是否通过抑制细胞衰老而促进肝癌的发生知之甚少。复制衰老模型和IR诱导的小鼠模型均显示TRAF2在衰老细胞或肝组织中的表达减少。TRAF2的缺失可能通过激活p53/p21WAF1和p16INK4a/PRB信号通路，抑制肝癌细胞的增殖，使细胞周期停滞，最终导致细胞衰老。在机制上，TRAF2缺乏增加线粒体蛋白活性氧调制子1(ROMO1)的表达，进而激活NAD+/SIRT3/SOD2通路，促进ROS的产生，导致线粒体功能障碍，最终导致DNA损伤反应(DDR)。我们的研究结果表明，TRAF2缺乏通过促进衰老来抑制肝癌的增殖。因此，通过多种途径靶向TRAF2具有治疗肝细胞癌的潜力。
The suppression of tumor proliferation via cellular senescence has emerged as a promising approach for anti-tumor therapy. Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adaptor protein involved in the NF-κB signaling pathway and reactive oxygen species (ROS) production, has been implicated in hepatocellular carcinoma (HCC) proliferation. However, little is currently known about whether TRAF2 promotes HCC development by inhibiting cellular senescence. Replicative senescence model and IR-induced mouse model demonstrated that TRAF2 expression was decrease in senescence cells or liver tissues. Depletion of TRAF2 could inhibit proliferation and arrest the cell cycle via activating p53/p21WAF1and p16INK4a/pRb signaling pathways in HCC cells and eventually lead to cellular senescence. Mechanistically, TRAF2 deficiency increased the expression of mitochondrial protein reactive oxygen species modulator 1 (ROMO1) and subsequently activated the NAD+/SIRT3/SOD2 pathway to promote the production of ROS and cause mitochondrial dysfunction, which eventually contributed to DNA damage response (DDR). Our findings demonstrate that TRAF2 deficiency inhibits the proliferation of HCC by promoting senescence. Therefore, targeting TRAF2 through various approaches holds therapeutic potential for treating HCC.