J Cancer 2019; 10(16):3735-3745. doi:10.7150/jca.32022

Research Paper

BDH2 is downregulated in hepatocellular carcinoma and acts as a tumor suppressor regulating cell apoptosis and autophagy

Hao Liang1,2#, Zhiyong Xiong2#, Ruixi Li3, Kunpeng Hu2, Mingbo Cao1, Jiarui Yang1, Zhaozhong Zhong1, Changchang Jia4, Zhicheng Yao2✉, Meihai Deng1✉

1. Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
2. Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
3. Department of Hepatobiliary Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518000, China
4. Department of Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
#These authors contributed equally to this work

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Citation:
Liang H, Xiong Z, Li R, Hu K, Cao M, Yang J, Zhong Z, Jia C, Yao Z, Deng M. BDH2 is downregulated in hepatocellular carcinoma and acts as a tumor suppressor regulating cell apoptosis and autophagy. J Cancer 2019; 10(16):3735-3745. doi:10.7150/jca.32022. Available from http://www.jcancer.org/v10p3735.htm

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Abstract

BDH2 is a short-chain dehydrogenase/reductase family member involved in several biological and pathological processes, including the utilization of cytosolic ketone bodies, immunocyte regulation and tumor progression. In this study, we first revealed that BDH2 was downregulated in HCC tissues by qRT-PCR and immunohistochemistry analysis and that low BHD2 expression was significantly associated with poor overall survival, poor tumor differentiation, increased tumor size, venous invasion and an advanced BCLC stage. Moreover, the results of a univariate analysis and multivariate analysis revealed that BDH2 may be regarded as an independent prognostic marker. As a member of a gene family involved in ketone metabolism, BDH2 upregulated the level of β-HB in liver cells as well as the level of H3 histone acetylation. Functional analysis showed that BDH2 expression inhibited tumor cell growth, proliferation and migration. The results of the mechanistic analysis revealed that BDH2 induced mitochondrial apoptosis and inhibited autophagy through the unfolded protein response. Therefore, BDH2 may be a new HCC prognostic marker and a useful treatment target.

Keywords: BDH2, hepatocellular carcinoma, tumor suppressor, apoptosis, autophagy