miR-31/QKI-5 axis facilitates cell cycle progression of non-small-cell lung cancer cells by interacting and regulating p21 and CDK4/6 expressions.

Abstract

BACKGROUND:

RNA-binding protein Quaking-5 (QKI-5), a major isoform of QKIs, inhibits tumor progression in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms of QKI-5 in the cell cycle of NSCLC are still largely unknown.

METHODS:

MTT, flow cytometry, and colony formation assays were used to investigate cellular phenotypic changes. Mice xenograft model was used to evaluate the antitumor activities of QKI-5. Co-immunoprecipitation, RNA immunoprecipitation (RIP), and RIP sequencing were used to investigate protein-protein interaction and protein-mRNA interaction.

RESULTS:

The QKI-5 expression was downregulated in NSCLC tissues compared with that in paired normal adjacent lung tissues. Overexpression of QKI-5 inhibited NSCLC cell proliferative and colony forming ability. In addition, QKI-5 induced cell cycle arrest at G0/G1 phase through upregulating p21Waf1/Cip1 (p21) expression and downregulating cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6 expressions. Further analyses showed that QKI-5 interacts with p21 protein and CDK4, CDK6 mRNAs, suggesting a critical function of QKI-5 in cell cycle regulation. In agreement with in vitro study, the mouse xenograft models validated tumor suppressive functions of QKI-5 in vivo through altering cell cycle G1-phase-associated proteins. Moreover, we demonstrated that QKI-5 is a direct target of miR-31. The QKI-5 expression was anticorrelated with the miR-31 expression in NSCLC patient samples.

CONCLUSION:

Our results suggest that the miR-31/QKI-5/p21-CDK4-CDK6 axis might have critical functions in the progression of NSCLC, and targeting this axis could serve as a potential therapeutic strategy for NSCLC.

• Authors: Wangyu Zhu, Yun Yu, Kexin Fang, Sisi Xiao, Lianli Ni, Changtian Yin, Xiangjie Huang, Xinchen Wang, Yongkui Zhang, Han-Bo Le, Ri Cui
• Journal: Cancer medicine (Cancer Med) Vol. 12 Issue 4 Pg. 4590-4604 (02 2023) ISSN: 2045-7634 [Electronic] United States
• PMID: 36172919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase Inhibitor p21
• MicroRNAs
• QKI protein, human
• RNA-Binding Proteins
• CDK4 protein, human
• MIRN31 microRNA, human

Topics

• Humans
• Animals
• Mice
• Carcinoma, Non-Small-Cell Lung (pathology)
• Lung Neoplasms (pathology)
• Cyclin-Dependent Kinase 4 (genetics)
• Cell Cycle (genetics)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Cell Line, Tumor
• MicroRNAs (genetics, metabolism)
• Cell Proliferation (genetics)
• Gene Expression Regulation, Neoplastic
• RNA-Binding Proteins (genetics, metabolism)