Abstract
BackgroundHydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver. Previous studies have suggested a role for dihydrotestosterone in modulating progress of various malignancies, and HSD17B6 dysfunction was associated with lung cancer and prostate cancer. However, little is known about the detailed role of HSD17B6 in hepatocellular carcinoma (HCC).MethodsClinical implication and survival data related to HSD17B6 expression in patients with HCC were obtained through TCGA, ICGC, ONCOMINE, GEO and HPA databases. Survival analysis plots were drawn with Kaplan–Meier Plotter. The ChIP-seq data were obtained from Cistrome DB. Protein–Protein Interaction and gene functional enrichment analyses were performed in STRING database. The correlations between HSD17B6 and tumor immune infiltrates was investigated via TIMER and xCell. The proliferation, migration and invasion of liver cancer cells transfected with HSD17B6 were evaluated by the CCK8 assay, wound healing test and transwell assay respectively. Expression of HSD17B6, TGFB1 and PD-L1 were assessed by quantitative RT-PCR.ResultsHSD17B6 expression was lower in HCC compared to normal liver and correlated with tumor stage and grade. Lower expression of HSD17B6 was associated with worse OS, PFS, RFS and DSS in HCC patients. HNF4A bound to enhancer and promoter regions of HSD17B6 gene, activating its transcription, and DNA methylation of HSD17B6 promoter negatively controlled the expression. HSD17B6 and its interaction partners were involved in androgen metabolism and biosynthesis in liver. HSD17B6 inhibited tumor cell proliferation, migration and invasion in liver cancer cells and low expression of HSD17B6 correlated with high immune cells infiltration, relative reduction of immune responses and multiple immune checkpoint genes expression in HCC, probably by regulating the expression of TGFB1.ConclusionsThis study indicate that HSD17B6 could be a new biomarker for the prognosis of HCC and an important negative regulator of immune responses in HCC.
Highlights
Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver
Our study indicated that transcription of HSD17B6 was positively regulated by hepatocyte nuclear factor 4 alpha (HNF4A), a liverenriched transcription factor
DNA hypermethylation of the HSD17B6 promoter contributed a lot to the low expression of HSD17B6 in Hepatocellular carcinoma (HCC)
Summary
Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver. Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide, with 700,000 annual deaths in recent years [1, 2]. It is the second most lethal tumor with only 18% of 5-year survival [3]. HCC is a clinically and biologically heterogeneous malignancy, most HCCs share common features regarding genetic and epigenetic alterations.
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