The TNF‐α‐induced expression of miR‐130b protects cervical cancer cells from the cytotoxicity of TNF‐α

• Published in: FEBS open bio 2018-04, Vol.8 (4), p.614-627
• Main Authors: Yang, Lei, Wang, Yanli, Shi, Shuainan, Xie, Lili, Liu, Tao, Wang, Yuliang, Mu, Hong
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell adhesion & migration; Cervical cancer; cervical cancer cell; Cervix; Colorectal cancer; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA methylation; Enzymes; Gene expression; MicroRNAs; miR‐130b; mRNA; Plasmids; PTEN; PTEN protein; TNF‐α resistance; Tumor cell lines; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12395

Tumour necrosis factor alpha (TNF‐α) is a multifunctional cytokine and has the capacity both to promote cell growth and to kill tumour cells by inducing cell apoptosis. However, many tumour cells develop resistance to the toxic effects of TNF‐α. Thus, understanding the mechanism underlying the resistance of tumours to TNF‐α toxicity and finding ways to overcome this resistance are urgently needed. In this study, we discovered that two cervical cancer cell lines, Hela and Siha, showed null responses to TNF‐α cytotoxicity. However, in these cell lines, TNF‐α stimulation promoted the expression of miR‐130b and downregulated the expression of PTEN gene, which encodes a dual‐specificity phosphatase that acts as a tumour suppressor. Blockade of miR‐130b function or overexpression of PTEN gene sensitized cells to TNF‐α cytotoxicity. Regression analyses revealed that there were reverse relationships between the cellular levels of miR‐130b and PTEN mRNA in cervical cancer cells. Gain‐ and loss‐of‐function assays demonstrated that there were causal relationships between the increase in miR‐130b levels and the reduction in PTEN mRNA or PTEN protein levels. In silico analysis revealed that there were two miR‐130b target sites within the 3′UTR of PTEN mRNA and experimental evidences demonstrated that miR‐130b repressed the expression of PTEN gene by binding directly to the 3′UTR of PTEN mRNA. These data suggest miR‐130b expression as a target to be inhibited to make tumour cells more sensitive to the toxic impact of TNF‐α. Tumour necrosis factor alpha (TNF‐α) stimulation induces the expression of miR‐130b in cervical cancer cells. Relying on the base pairing between its seed sequence and target site, miR‐130b binds to the 3′UTR of PTEN mRNA and impairs the expression of PTEN gene that desensitizes cells to TNF‐α cytotoxicity, characterized as reduced cell viability and an increase in the rate of apoptosis.