Abstract
Lung adenocarcinoma is one of the most frequent tumor subtypes, involving changes in a variety of oncogenes and tumor suppressor genes. Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) could synthetize dihydrotestosterone, abnormal levels of which are associated with progression of multiple tumors. Previously, we showed that HSD17B6 inhibits malignant progression of hepatocellular carcinoma. However, the mechanisms underlying inhibiting tumor development by HSD17B6 are not clear. Moreover, its role in lung adenocarcinoma (LUAD) is yet unknown. Here, we investigated its expression profile and biological functions in LUAD. Analysis of data from the LUAD datasets of TCGA, CPTAC, Oncomine, and GEO revealed that HSD17B6 mRNA and protein expression was frequently lower in LUAD than in non-neoplastic lung tissues, and its low expression correlated significantly with advanced tumor stage, large tumor size, poor tumor differentiation, high tumor grade, smoking, and poor prognosis in LUAD. In addition, its expression was negatively regulated by miR-31-5p in LUAD. HSD17B6 suppressed LUAD cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and radioresistance. Furthermore, HSD17B6 overexpression in LUAD cell lines enhanced PTEN expression and inhibited AKT phosphorylation, inactivating downstream oncogenes like GSK3β, β-catenin, and Cyclin-D independent of dihydrotestosterone, revealing an underlying antitumor mechanism of HSD17B6 in LUAD. Our findings indicate that HSD17B6 may function as a tumor suppressor in LUAD and could be a promising prognostic indicator for LUAD patients, especially for those receiving radiotherapy.
Highlights
More than 2.2 million patients were diagnosed with lung cancer in 2020, making it the second most common tumor worldwide
Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) expression is downregulated in lung adenocarcinoma (LUAD) tissues In order to investigate the potential role of HSD17B6 in tumors, We first analyzed the differential expression of HSD17B6 between tumor tissues and corresponding non-tumor tissues in the 32 cancers included in TCGA [13]
The analysis revealed that HSD17B6 expression was substantially lower in 11 kinds of tumors compared to the non-tumor tissues, including LUAD (Lung Adenocarcinoma), LUSC (Lung Squamous Cell Carcinoma), and so on (Fig. 1A)
Summary
More than 2.2 million patients were diagnosed with lung cancer in 2020, making it the second most common tumor worldwide. It caused about 1.8 million deaths in 2020 globally and ranked as the first leading cause of cancer-associated death [1]. 50% of lung cancers are LUAD, which is the most common subtype [2]. The aggressiveness is often driven by molecular genetic/ epigenetic abnormalities in LUAD.
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