The lipid transporter HDLBP promotes hepatocellular carcinoma metastasis through BRAF-dependent epithelial-mesenchymal transition.

Tumor metastasis is a major cause of cancer mortality. However, little is known regarding the regulation of abnormal cholesterol metabolism in hepatocellular carcinoma (HCC) metastasis. Here, we show that the expression of high-density lipoprotein binding protein (HDLBP), a lipid transporter, is clinically correlated with tumor metastasis in HCC patients. Moreover, ...
HDLBP was required for cholesterol-induced HCC metastasis. We revealed that knockdown and overexpression of HDLBP significantly inhibited and enhanced, respectively, the metastasis, invasion and epithelial-mesenchymal transition (EMT) of HCC cells in vitro and in vivo. Mechanistically, coimmunoprecipitation and mass spectrometry screening uncovered BRAF as a protein target of HDLBP. HDLBP was found to promote EMT signaling in a BRAF-dependent manner. Furthermore, HDLBP interacts with BRAF and inhibits its ubiquitinated degradation by abrogating BRAF-ITCH interactions. Notably, further studies suggest that dabrafenib exhibited a greater metastasis-suppressive effect in HDLBP knockout HCC than isolated treatment. Overall, our findings imply that cholesterol-induced HDLBP contributes to the metastasis and invasion of HCC through BRAF-dependent EMT signaling and that HDLBP may be applied as a biomarker and therapeutic target for HCC.
Mesh Terms:
Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Movement, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Lipids, Lipoproteins, HDL, Liver Neoplasms, Neoplasm Invasiveness, Neoplasm Metastasis, Proto-Oncogene Proteins B-raf, RNA-Binding Proteins
Cancer Lett
Date: Nov. 28, 2022
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