脂肪生成
甾醇调节元件结合蛋白
癌症研究
细胞生长
安普克
肿瘤进展
内科学
生物
细胞生物学
蛋白激酶A
肝细胞癌
内分泌学
癌症
激酶
脂质代谢
甾醇
生物化学
医学
胆固醇
作者
Chenchen Wang,Ying Tong,Yankai Wen,Jie Cai,Han Guo,Lifeng Huang,Min Xu,Feng Mao,Xiaosong Chen,Jianjun Zhang,Hailong Wu,Xiaoni Kong,Qiang Xia
出处
期刊:Hepatology
[Wiley]
日期:2018-09-19
卷期号:68 (5): 1833-1850
被引量:34
摘要
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Increased lipogenesis has been reported to play a critical role in HCC progression. However, the underlying mechanism contributing to lipogenesis increase in HCC remains elusive. Here, we show that HCC-associated protein TD26 (TD26) was highly expressed in HCC tumor tissues compared to matched normal tissues. From the clinicopathologic analyses of two independent HCC cohorts, we demonstrate that TD26 expression was positively correlated with tumor size and was an independent predictor of overall survival (OS) and recurrence-free survival (RFS) in HCC patients. Our metabolomics assays demonstrate that TD26 had no effect on glycometabolism, but significantly increased lipogenesis in HCC cells. In addition, our functional assays indicate that TD26 promoted HCC cell proliferation and tumor growth. We further demonstrate that TD26-mediated increase in lipogenesis and tumor cell proliferation was SREBP1 dependent. Mechanistically, we demonstrate that, through its C-terminus (amino acids [aa] from 121 to 198), TD26 interacted with the truncated nuclear sterol regulatory element-binding protein 1 (SREBP1) form (nSREBP1), but not full-length SREBP1 (flSREBP1), to block adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mediated inhibition on SREBP1 activity, resulting in increased lipogenesis, elevated tumor cell proliferation, and enhanced tumor progression. Conclusion: We propose that TD26 is a positive regulator on SREBP1 transactivity, and the interaction between TD26 and SREBP1 can serve as a potential therapeutic target for HCC treatment.
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