Hypomethylation-driven AKT Serine/Threonine Kinase 3 promotes testicular germ cell tumors proliferation and negatively correlates to immune infiltration

Yang Luo; Qianyin Zhou; Fang Zhu; Liqing Fan; Hao Bo; Xingming Wang

doi:10.1080/21655979.2021.2002621

Hypomethylation-driven AKT Serine/Threonine Kinase 3 promotes testicular germ cell tumors proliferation and negatively correlates to immune infiltration

Bioengineered. 2021 Dec;12(2):11288-11302. doi: 10.1080/21655979.2021.2002621.

Authors

Yang Luo^{1

2}, Qianyin Zhou³, Fang Zhu³, Liqing Fan^{3

4}, Hao Bo^{3

4}, Xingming Wang⁵

Affiliations

¹ Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
² Key Laboratory for Reproductive Medicine of Guangdong Province, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
³ NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
⁴ Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China.
⁵ Department of Nuclear Medicine (Pet Center), Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

AKT Serine/Threonine Kinase 3 (AKT3) has been reported to play an important role in different tumors. However, its clinical value, biological function, and molecular mechanism in testicular germ cell tumors (TGCT) remains unclear. In the current study, we applied the Gene Set Cancer Analysis (GSCA), UCSC XENA, Gene Expression Omnibus (GEO), the Human Protein Atlas (HPA), LinkedOmics, DiseaseMeth version 2.0, TISIDB, and other databases for TGCT data mining. Then, we investigated AKT3's mechanism of action and clinical survival significance via bioinformatics followed by in vitro experiments. We found that AKT3 was upregulated and had frequent copy number amplifications in TGCT, which were associated with poor survival outcomes of patients. On the other hand, mutations that led to AKT3 loss-of-function were correlated to a better prognosis in patients. Moreover, AKT3 silencing significantly inhibited the proliferation, DNA synthesis and colony formation of NCCIT cells (a TGCT cell line). AKT3 might participate in TGCT progression through multiple signaling pathways, such as ErbB, oxidative phosphorylation, and affecting tumor immune infiltration. Also, the upregulation of AKT3 mRNA expression might be driven by the hypomethylation of its promoter region. Overall, AKT3 is a potential TGCT oncogene and can be further used as a therapeutic target.

Keywords: AKT3; TGCT; immunity; methylation; proliferation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics
DNA Methylation / drug effects
DNA Methylation / genetics*
Follow-Up Studies
Gene Dosage
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lymphocytes, Tumor-Infiltrating
Mutation / genetics
Neoplasms, Germ Cell and Embryonal / genetics*
Neoplasms, Germ Cell and Embryonal / immunology*
Neoplasms, Germ Cell and Embryonal / pathology
Prognosis
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Signal Transduction / drug effects
Survival Analysis
Testicular Neoplasms / genetics*
Testicular Neoplasms / immunology*
Testicular Neoplasms / pathology
Treatment Outcome

Substances

Protein Kinase Inhibitors
RNA, Messenger
AKT3 protein, human
Proto-Oncogene Proteins c-akt

Supplementary concepts

Testicular Germ Cell Tumor

Grants and funding

This study was supported by the Changsha Municipal Natural Science Foundation (kq2014033), the Natural Science Foundation of Hunan Province (2021JJ41025), the Guangzhou Municipal/University (High-Level University) Joint Funded Basic Research Program (202102010055), the Guangdong Basic and Applied Basic Research Foundation (2019A1515010755), the Medical Key Discipline of Guangzhou (2021-2023) and the Hunan Provincial Grant for Innovative Province Construction (2019SK4012).