Enhancing cisplatin chemosensitivity in gastric cancer through LINC00162 silencing: Modulation of the PI3K/AKT pathway and NANOG downregulation

Abstract

Introduction: Chemotherapy drugs serve as one of the primary treatments for gastric cancer. However, challenges, including drug resistance and adverse side effects of the chemotherapy drugs like cisplatin, limit their efficacy. Long non-coding RNAs (lncRNAs) have been increasingly recognized as important regulators in oncogenesis and drug response. In this study, the potential effect of the long non-coding RNA LINC00162 (PICSAR) on modulating the chemosensitivity of gastric cancer cells to cisplatin was investigated. Furthermore, the impact of the LINC00162 silencing on cellular responses was evaluated under two conditions: after the siRNA-mediated silencing of the LINC00162 alone, and after combined treatment with cisplatin.
Methods: Firstly, the viability of the cells following siRNA-mediated LINC00162 silencing, treatment with cisplatin, and the combination of both was evaluated. Half inhibitory concentration (IC₅₀) of the cisplatin chemotherapy drug was assessed individually and after silencing of the LINC00162 via siRNA. Additionally, we investigated apoptosis, cell cycle arrest, migration, and colony formation in the cancer cells following the combination treatment. Finally, the effect of the combination treatment on the expression of the genes involved in these pathways, including BAX, BCL2, TP53, MMP-9, CASP3, CASP9, AKT, PI3K, and NANOG was evaluated by qRT-PCR.
Results: Findings indicated that LINC00162 silencing increased the sensitivity of the AGS gastric cancer cells to cisplatin and reduced the IC₅₀ of cisplatin from 19.24 µg/mL to 14.08 µg/mL. Furthermore, LINC00162 siRNA induced apoptosis, increasing the apoptosis rate to 10.69% compared to 6.19% in the control group, and also caused sub-G₁ cell cycle arrest (3.94%). This effect was significantly enhanced in the combination treatment group (apoptosis: 41.7% and Sub-G1 arrest: 17.3%) compared to the control group or either single treatment. Moreover, our study demonstrated that siRNA-mediated inhibition of the LINC00162, both individually and in combination with cisplatin, decreased the migration and colony formation ability of AGS cancer cells.
Conclusion: These findings suggest that targeting LINC00162 may potentially enhance the efficacy of cisplatin in gastric cancer cells and may represent a promising therapeutic strategy for gastric cancer.

Keywords: LncRNA, Combination therapy, Gastric cancer, Cisplatin, Apoptosis, Metastasis