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.
Background
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]. Approximately 50% of lung cancers are LUAD, which is the most common subtype [2]. Although new therapeutic strategies, such as targeted therapies, have achieved remarkable improvements in recent years, LUAD is still one of the most aggressive and fatal tumor types with overall survival 50 cells were counted. The surviving fraction was calculated as previously described [60].
Western blotting
For preparing cell lysates for western blotting, cells were lysed in ice-cold cell lysis buffer and centrifuged to remove cell debris. Nuclear and cytoplasmic fractions were extracted from the cell pellets as previously described [61]. After electrophoresis, proteins were transferred to a PVDF membrane. After blocking, membranes were incubated with the following primary antibodies: GAPDH [ProteinTech #60004-1-Ig], HSD17B6 [ProteinTech #11855-1-AP], AKT [CST #C6717], p-AKT [Ser473] [CST #4060], PTEN [ProteinTech #22034-1-AP], MMP2 [ProteinTech #10373-2-AP], MMP9 [ProteinTech #10375-2-AP], E-cadherin [ProteinTech #20874-1-AP], N-cadherin [ProteinTech #66219-1-Ig], Vimentin [ProteinTech #10366-1-AP], snail [CST #3895], survivin [CST #2808], GSK3β [ProteinTech #22104-1-AP], p-GSK3β [CST #9322], β-catenin [CST #8480], cyclin D1 [ProteinTech #60186-1-Ig], cyclin E1 [ProteinTech #11554-1-AP], PCNA [ProteinTech #10205-2-AP], and Lamin A/C [ProteinTech #10298-1-AP] overnight at 4 ˚C. Then, the membranes were incubated with secondary antibodies: HRP-conjugated anti‑rabbit IgG [ProteinTech #SA00001‑2] or anti‑mouse IgG [ProteinTech #SA00001‑1] for 1 h at room temperature. All the experiments were performed in triplicate.
BSP analysis
BSP analysis was performed as previously described [62]. Briefly, genomic DNA was extracted from cells, then qualified and quantified by a NanoPhotometer [IMPLEN]. The bisulfite conversion was carried out using EZ DNA Methylation-Gold Kit [cat. no. D5006; ZYMO Research]. Upstream CpG Island of HSD17B6 gene was amplified using the primers listed below: forward, 5′-GATAGTATTGAGAGTAGGGAAAGAG-3′ and reverse, 5′-TTCTACCCACAAAAACRATAAC-3′. The PCR products from bisulfite-treated DNA were cloned into T- vector and then sequenced.
Luciferase reporter assay
A full length of the human HSD17B6 3′-untranslated region [449 bp] with the miR-31-5p targeting sequence was cloned downstream of the firefly luciferase gene in pGL3-control [Invitrogen] to construct pGL3-luc-HSD17B6. Then, the luciferase activity was determined as previously described [63].
Gene set enrichment analysis [GSEA]
Spearman’s correlation coefficient between the mRNA levels of each gene and HSD17B6 levels was computed and used to create a ranked gene list, which was supplied to pre-ranked analysis on HALLMARK-term database [h.all.v7.3.symbols.gmt] of Molecular Signatures Database [MSigDB] using GSEA software [v4.1.0]. Statistically significant pathways were screened based on the 0.35 as the cutoff criteria [64].
Statistical analysis
Data are presented as mean ± standard deviation. Differences between the two groups were evaluated using the two-sided Student’s t-test for normally distributed data or Mann–Whitney test for non-normally distributed data. F-test was used to compare the variance of two samples before Student’s t-test. Normality of data was determined by Kolmogorov–Smirnov test. Correlation analysis was performed using the Pearson’s test. Statistical analysis was performed with packages in R software or Prism 8.3.4 [GraphPad]. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05. All data were analyzed blindly.
Data availability
The data that support the findings of the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China [81602230 to LL, 81402327 to QYY, 11805228 to NC], the Provincial Natural Science Research Project of Anhui Colleges [KJ2020A0147 to QYY], and The Youth Fund of Anhui Cancer Hospital [2020YJQN005 to TT].
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Authors and Affiliations
Department of Respiratory Oncology, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, People’s Republic of China
Tian Tian
Department of Radiation Oncology, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, People’s Republic of China
Fu Hong
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
Zhiwen Wang & Jiaru Hu
School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of China
Ni Chen & Qiyi Yi
Department of Cancer Epigenetics Program, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, People’s Republic of China
Lei Lv
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- Tian Tian
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- Fu Hong
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- Zhiwen Wang
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Contributions
QY and LL conceived and designed the study. QY and LL wrote the manuscript. TT, FH, and NC performed the experiments. WZ and HJ generated and analyzed the bioinformatics data. All authors read and approved the final manuscript.
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Tian, T., Hong, F., Wang, Z. et al. HSD17B6 downregulation predicts poor prognosis and drives tumor progression via activating Akt signaling pathway in lung adenocarcinoma. Cell Death Discov. 7, 341 [2021]. //doi.org/10.1038/s41420-021-00737-0
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Received: 10 August 2021
Revised: 23 October 2021
Accepted: 26 October 2021
Published: 08 November 2021
DOI: //doi.org/10.1038/s41420-021-00737-0