Xu Jingwen, Li Yue, Wang Guangyan, Chen Dapeng, Hou Chenxue, Wang Rui, Dong Wenhui, Sun Lei, Yang Kun, Duan Jinjie, Pu Guangyin, Zhao Xiaoyu, Ai Rong, Xiu Wenjing, Wang Qi, Wang Chunjiong
Department of Physiology and Pathophysiology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Oncogene. 2025 Jun;44(20):1475-1487. doi: 10.1038/s41388-025-03321-3. Epub 2025 Mar 1.
Metabolic dysfunction-associated steatohepatitis (MASH) is the fastest-growing cause of liver cancer. The liver microenvironment of patients with MASH supports the development of hepatocellular carcinoma (HCC). Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2), which is located in both the mitochondria and nucleus, is increased in MASH liver. Its role in the development of MASH-HCC remain unknown. In this study, we found CHCHD2 protein levels were elevated in both tumor and para-tumor tissues of patients with MASH-HCC and diethylnitrosamine- and high-fat diet-induced MASH-HCC mice. Chchd2-knockout mice were generated. CHCHD2 was overexpressed in hepatocytes using AAV with TBG promoter. Chchd2 knockout inhibited the progression of MASH-HCC in mice. CHCHD2 protein-targeted ChIP-sequencing data revealed that CHCHD2 target genes encoding secretory proteins were enriched in cancer pathways. Among these genes, vascular endothelial growth factor A (VEGFA) level increased in CHCHD2-overexpressing livers and hepatocytes. Chchd2 knockdown reduced palmitate-induced VEGFA expression. Palmitate-treated hepatocyte increased the angiogenic activity of endothelial cells in a paracrine manner, and this was suppressed by Chchd2 knockdown in hepatocytes. CHCHD2-overexpressing hepatocytes promoted the angiogenic activity of endothelial cells. We futher employed an orthotopic murine model of HCC to demonstrate that elevated CHCHD2 protein levels in para-tumor tissues support HCC growth. In addition, we found that the degradation of CHCHD2 was primarily mediated by mitochondrial protease ClpXP, which was repressed in the MASH liver. In conclusion, the mitochondrial degradation of CHCHD2 is impaired in MASH, and elevated CHCHD2 levels in hepatocytes promote VEGFA transcription and support the growth of HCC.
代谢功能障碍相关脂肪性肝炎（MASH）是肝癌增长最快的病因。MASH患者的肝脏微环境促进肝细胞癌（HCC）的发展。含卷曲螺旋-螺旋-卷曲螺旋-螺旋结构域2（CHCHD2）位于线粒体和细胞核中，在MASH肝脏中表达增加。其在MASH-HCC发展中的作用尚不清楚。在本研究中，我们发现CHCHD2蛋白水平在MASH-HCC患者的肿瘤组织和癌旁组织以及二乙基亚硝胺和高脂饮食诱导的MASH-HCC小鼠中均升高。我们构建了Chchd2基因敲除小鼠。使用具有TBG启动子的腺相关病毒（AAV）在肝细胞中过表达CHCHD2。Chchd2基因敲除抑制了小鼠MASH-HCC的进展。CHCHD2蛋白靶向的染色质免疫沉淀测序数据显示，CHCHD2的靶基因编码分泌蛋白，在癌症通路中富集。在这些基因中，血管内皮生长因子A（VEGFA）水平在CHCHD2过表达的肝脏和肝细胞中升高。Chchd2基因敲低降低了棕榈酸酯诱导的VEGFA表达。棕榈酸酯处理的肝细胞以旁分泌方式增加内皮细胞的血管生成活性，而肝细胞中的Chchd2基因敲低可抑制这种活性。CHCHD2过表达的肝细胞促进内皮细胞的血管生成活性。我们进一步采用肝癌原位小鼠模型证明，癌旁组织中CHCHD2蛋白水平升高促进肝癌生长。此外，我们发现CHCHD2的降解主要由线粒体蛋白酶ClpXP介导，而ClpXP在MASH肝脏中受到抑制。总之，MASH中CHCHD2的线粒体降解受损，肝细胞中CHCHD2水平升高促进VEGFA转录并支持肝癌生长。
