Downexpression of HSD17B6 correlates with clinical prognosis and tumor immune infiltrates in hepatocellular carcinoma

Abstract

Background Hydroxysteroid 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). Methods Clinical 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. Results HSD17B6 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. Conclusions This study indicate that HSD17B6 could be a new biomarker for the prognosis of HCC and an important negative regulator of immune responses in HCC.

A Novel Prognostic Signature Based on Metabolism-Related Genes to Predict Survival and Guide Personalized Treatment for Head and Neck Squamous Carcinoma

“…HS3ST1 might acts as a molecular biomarker for tumor diagnosis and prognosis ( 35 ). HSD17B6 has important functionality in androgen catabolism and was remarkably downregulated in hepatocellular carcinoma, which predicted poor prognosis and high tumor immune infiltrates ( 36 ). It was identified that LIPE is up-regulated in cervical cancer and promotes cell proliferation, invasion, and epithelial-mesenchymal transformation ( 37 ).…”

The expression and prognostic value of REXO4 in hepatocellular carcinoma

“…Ten genes related to REXO4 were shown in Figure 9, among them, HSD17B6, URM1, HPX, C6, ZMYND19 were playing a key part in the advancement of liver cancer (12)(13)(14)(15)(16). In an attempt to gain valuable insight regarding the biological importance of REXO4 in HCC, REXO4 co-expression mode in the LIHC cohort was examined Tumor Tissue Normal Tissue using the function module of LinkedOmics.…”

Identification of an Individualized Metabolism Prognostic Signature and Related Therapy Regimens in Early Stage Lung Adenocarcinoma

“…Among the DEGs from the three cohorts, three MRGs (B3GNT3, ADH1B, and HSD17B6) were overlapped (Figures 5A-C), and their expression levels were significantly correlated with MRGPI (Supplementary Figure S6). The three MRGs had been reported to be associated with other cancers (17)(18)(19), but few studies reported their role in LUAD.…”

“…HSD17B6 could convert 3 alpha-adiol to dihydrotestosterone that was closely related to the development of many tumors (20). Lv et al (17) reported that low expression of HSD17B6 correlated with multiple ICGs expression in hepatocellular carcinoma. In this study, we observed that the expression level of HSD17B6 was negatively correlated with PD-1 (r = −0.20 and P < 0.001 in TCGA, r = −0.19 and P < 0.001 in GSE72094), PD-L1 (r = −0.11 and P = 0.033 in TCGA, r = −0.14 and P = 0.003 in GSE72094), and LAG3 (r = −0.22 and P < 0.001 in TCGA, r = -0.21 and P < 0.001 in GSE72094) (Figure 5H), suggesting that low HSD17B6 expression potentially played an important role in mediating immune evasion.…”