microRNA-196a-5p inhibits testicular germ cell tumor progression via NR6A1/E-cadherin axis.

Abstract

Testicular germ cell tumors (TGCTs) are a diverse group of neoplasms that are derived from dysfunctional fetal germ cells and can also present in extragonadal sites. The genetic drivers underlying malignant transformation of TGCTs have not been fully elucidated so far. The aim of the present study is to clarify the functional role and regulatory mechanism of miR-196a-5p in TGCTs. We demonstrated that miR-196a-5p was downregulated in TGCTs. It can inhibit the proliferation, migration, and invasion of testicular tumor cell lines including NT-2 and NCCIT through targeting the NR6A1 gene, which we proved its role in promotion of cell proliferation and repression of cellular junction and aggregation. Mechanistically, NR6A1 inhibited E-cadherin through binding with DR0 sites in the CDH1 gene promoter and recruiting methyltransferases Dnmt1. Further, NR6A1 promoted neuronal marker protein MAP2 expression in RA-induced neurodifferentiation of NT-2 cells and testicular tumor xenografts. Clinical histopathologically, NR6A1 was positively correlated with MAP2, and negatively correlated with E-cadherin in TGCTs. These findings revealed that the miR-196a-5p represses cell proliferation, migration, invasion, and tumor neurogenesis by inhibition of NR6A1/E-cadherin signaling axis, which may be a potential target for diagnosis and therapy of TGCTs.

• Authors: Xiaowen Liu, Ziling Fan, Ye Li, Zhilan Li, Zhuan Zhou, Xuehui Yu, Jingyu Wan, Ziqian Min, Lifang Yang, Dan Li
• Journal: Cancer medicine (Cancer Med) Vol. 9 Issue 23 Pg. 9107-9122 (12 2020) ISSN: 2045-7634 [Electronic] United States
• PMID: 33034957 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• MIRN196 microRNA, human
• MicroRNAs
• NR6A1 protein, human
• Nuclear Receptor Subfamily 6, Group A, Member 1
• DNA (Cytosine-5-)-Methyltransferase 1
• DNMT1 protein, human

Topics

• Animals
• Antigens, CD (genetics, metabolism)
• Cadherins (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• DNA (Cytosine-5-)-Methyltransferase 1 (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasms, Germ Cell and Embryonal (genetics, metabolism, pathology)
• Neurogenesis
• Nuclear Receptor Subfamily 6, Group A, Member 1 (genetics, metabolism)
• Signal Transduction
• Testicular Neoplasms (genetics, metabolism, pathology)