Antitumor activity of miR-188-3p in gastric cancer is achieved by targeting CBL expression and inactivating the AKT/mTOR signaling

Jian-Jiao Lin; Bao-Hua Luo; Tao Su; Qiong Yang; Qin-Fei Zhang; Wei-Yu Dai; Yan Liu; Li Xiang

doi:10.4251/wjgo.v15.i8.1384

Antitumor activity of miR-188-3p in gastric cancer is achieved by targeting CBL expression and inactivating the AKT/mTOR signaling

World J Gastrointest Oncol. 2023 Aug 15;15(8):1384-1399. doi: 10.4251/wjgo.v15.i8.1384.

Authors

Jian-Jiao Lin¹, Bao-Hua Luo², Tao Su¹, Qiong Yang³, Qin-Fei Zhang¹, Wei-Yu Dai⁴, Yan Liu¹, Li Xiang⁵

Affiliations

¹ Department of Gastroenterology, The Second Affiliated Hospital of Chinese University of Hong Kong (Shenzhen Longgang District People's Hospital), Shenzhen 518172, Guangdong Province, China.
² Department of Urology, Hospital of Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China.
³ Department of Gastroenterology, The Second Affiliated Hospital of the University of South China, Hengyang 421001, Hunan Province, China.
⁴ Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
⁵ Department of Gastroenterology, The Second Affiliated Hospital of Chinese University of Hong Kong (Shenzhen Longgang District People's Hospital), Shenzhen 518172, Guangdong Province, China.shellyxiangli@163.com.

Abstract

Background: Altered miR-188-3p expression has been observed in various human cancers.

Aim: To investigate the miR-188-3p expression, its roles, and underlying molecular events in gastric cancer.

Methods: Fifty gastric cancer and paired normal tissues were collected to analyze miR-188-3p and CBL expression. Normal and gastric cancer cells were used to manipulate miR-188-3p and CBL expression through different assays. The relationship between miR-188-3p and CBL was predicted bioinformatically and confirmed using a luciferase gene reporter assay. A Kaplan-Meier analysis was used to associate miR-188-3p or CBL expression with patient survival. A nude mouse tumor cell xenograft assay was used to confirm the in vitro data.

Results: MiR-188-3p was found to be lower in the plasma of gastric cancer patients, tissues, and cell lines compared to their healthy counterparts. It was associated with overall survival of gastric cancer patients (P < 0.001), tumor differentiation (P < 0.001), lymph node metastasis (P = 0.033), tumor node metastasis stage (I/II vs III/IV, P = 0.024), and American Joint Committee on Cancer stage (I/II vs III/IV, P = 0.03). Transfection with miR-188-3p mimics reduced tumor cell growth and invasion while inducing apoptosis and autophagy. CBL was identified as a direct target of miR-188-3p, with its expression antagonizing the effects of miR-188-3p on gastric cancer (GC) cell proliferation by inducing tumor cell apoptosis and autophagy through the inactivation of the Akt/mTOR signaling pathway. The in vivo data confirmed antitumor activity via CBL downregulation in gastric cancer.

Conclusion: The current data provides ex vivo, in vitro, and in vivo evidence that miR-188-3p acts as a tumor suppressor gene or possesses antitumor activity in GC.

Keywords: AKT/mTOR signaling pathway; Autophagy; CBL expression; Gastric cancer; Tumor cell proliferation; miR-188-3p.