索拉非尼
肝细胞癌
医学
内科学
胆固醇
癌症研究
载脂蛋白E
肿瘤科
疾病
作者
Shan Wan,Quan-Yao He,Yun Yang,Feng Liu,Xue Zhang,Xin Guo,Hui Niu,Yi Wang,Yi-Xuan Liu,Wen-Long Ye,Xiuming Li,Xue-Mei ZhuanSun,Pu Sun,Xiao‐Shun He,Gang Hu,Kai Breuhahn,Hua Zhao,Guo-Qiang Wu,Hua Wu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-03-12
卷期号:84 (11): 1872-1888
被引量:3
标识
DOI:10.1158/0008-5472.can-23-2889
摘要
Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastases. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC (secreted protein acidic and rich in cysteine) was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC.
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