miR-497 defect contributes to gastric cancer tumorigenesis and progression via regulating CDC42/ITGB1/FAK/PXN/AKT signaling

Lihui Zhang; Liwen Yao; Wei Zhou; Jinping Tian; Banlai Ruan; Zihua Lu; Yunchao Deng; Qing Li; Zhi Zeng; Dongmei Yang; Renduo Shang; Ming Xu; Mengjiao Zhang; Du Cheng; Yanning Yang; Qianshan Ding; Honggang Yu

doi:10.1016/j.omtn.2021.07.025

miR-497 defect contributes to gastric cancer tumorigenesis and progression via regulating CDC42/ITGB1/FAK/PXN/AKT signaling

Mol Ther Nucleic Acids. 2021 Aug 8:25:567-577. doi: 10.1016/j.omtn.2021.07.025. eCollection 2021 Sep 3.

Authors

Lihui Zhang^{1

2

3}, Liwen Yao^{1

2

3}, Wei Zhou^{1

2

3}, Jinping Tian⁴, Banlai Ruan⁴, Zihua Lu^{1

2

3}, Yunchao Deng^{1

2

3}, Qing Li^{1

2

3}, Zhi Zeng⁵, Dongmei Yang^{1

2

3}, Renduo Shang^{1

2

3}, Ming Xu^{1

2

3}, Mengjiao Zhang^{1

2

3}, Du Cheng^{1

2

3}, Yanning Yang⁶, Qianshan Ding^{1

2

3

4}, Honggang Yu^{1

2

3}

Affiliations

¹ Department of Gastroenterology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, Hubei 430060, PR China.
² Hubei Key Laboratory of Digestive System, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
³ Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
⁴ Medical Research Center, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Weiyang District, Xi'an, Shaanxi 710016, PR China.
⁵ Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
⁶ Department of Ophthalmology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, Hubei 430060, PR China.

Abstract

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. MicroRNAs (miRNAs) are known to be important regulators of GC. This study aims to investigate the role of miRNA (miR)-497 in GC. We demonstrated that the expression of miR-497 was downregulated in human GC tissues. After N-methyl-N-nitrosourea treatment, the incidence of GC in miR-497 knockout mice was significantly higher than that in wild-type mice. miR-497 overexpression suppressed GC cell proliferation, cell-cycle progression, colony formation, anti-apoptosis ability, and cell migration and invasion capacity. Additionally, miR-497 overexpression decreased the expression levels of cell division cycle 42 (CDC42) and integrin β1 (ITGB1) and inhibited the phosphorylation of focal adhesion kinase (FAK), paxillin (PXN), and serine-threonine protein kinase (AKT). Furthermore, overexpression of miR-497 inhibited the metastasis of GC cells in vivo, which could be counteracted by CDC42 restoration. Furthermore, the focal adhesion of GC cells was found to be regulated by miR-497/CDC42 axis via ITGB1/FAK/PXN/AKT signaling. Collectively, it is concluded that miR-497 plays an important role in the repression of GC tumorigenesis and progression, partly via the CDC42/ITGB1/FAK/PXN/AKT pathway.

Keywords: CDC42; focal adhesion kinase; gastric cancer; miR-497; paxillin; tumorigenesis.