Tumor suppressor ZHX2 inhibits NAFLD\u2013HCC progression via blocking LPL-mediated lipid uptake

Zhuanchang Wu,Hongxin Ma,Chunyang Li,Yankun Zhang,Nailin Li,Xiaojia Song,Jianping Wang,Yutong Ge,Chunhong Ma,Wen Liu,Yang Sun,Xuetian Yue,Xiangguo Yu,Lifen Gao,Liyuan Wang,Xiaohong Liang,Jie Zhang,Zehua Wang

doi:10.1038/s41418-019-0453-z

Zhuanchang Wu, Hongxin Ma + Show 16 more

Open Access

https://doi.org/10.1038/s41418-019-0453-z

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Abstract

Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD–HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD–HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide
Liver tissue with vacuolation is a sign of lipid deposition [21], above results indicated that lipids may regulate Zinc fingers and homeoboxes 2 (ZHX2) expression
Consistent with the in vitro assays, mRNA, and protein levels of ZHX2 were significantly decreased in MCD diet- and HFD-induced fatty livers compared with livers from non-fat diet (NFD) fed mice (Fig. 1c)

Summary

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. TP53, a TSG and one of the most frequently mutated genes in HCC, inhibits the expression of cellular metabolism-regulating genes to prevent tumor development [6]. Identifying TSGs involved in the regulation of lipid metabolisms would be beneficial for understanding mechanisms of NAFLD-related carcinogenesis of HCC. We found that ZHX2 inhibited uptake of exogenous lipids in hepatocytes and suppressed NAFLD progression by transcriptionally repressing lipid lipase (LPL) expression. The latter caused cell growth retardation, and inhibited progression of NAFLD to HCC. These findings provide potential therapeutic targets for NAFLDassociated HCC

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Results

Discussion

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