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Downregulation of microRNA-4295 Enhances Cisplatin-Induced Gastric Cancer Cell Apoptosis Through the EGFR/PI3K/Akt Signaling Pathway by Targeting LRIG1

Downregulation of microRNA-4295 Enhances Cisplatin-Induced Gastric Cancer Cell Apoptosis Through the EGFR/PI3K/Akt Signaling Pathway by Targeting LRIG1

Rong Yan, Kang Li, Da-Wei Yuan, Hao-Nan Wang, Yong Zhang, Cheng-Xue Dang, Kun Zhu

Int J Oncol. 2018 Dec;53(6):2566-2578.

PMID: 30320337

Abstract:

Gastric cancer (GC) is one of the leading causes of cancer-associated mortality worldwide. The aim of the present study was to investigate the mechanism of microRNA-4295 (miR-4295), which regulates cisplatin (DDP)-induced apoptosis in GC cells through the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1)-mediated epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Two cell lines were selected, one with the highest expression of miR-4295 and one with the lowest expression of LRIG1, for the experiments. The half maximal inhibitory concentration of DDP in the human GC MKN-28 and MKN-45 cell lines was calculated, and mitochondrial membrane potentials of the GC cells were detected by tetramethylrhodamine, ethyl ester, perchlorate staining. The proliferation and apoptosis of GC cells with or without DDP treatment were assessed by MTT assay and plate colony formation, as well as flow cytometry and TUNEL staining. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were employed to determine the expression of EGFR/PI3K/Akt signaling pathway-related genes and apoptosis-related genes. LRIG1 was identified as a target gene of miR-4295. The expression of miR-4295 was upregulated, and the expression of LRIG1 was downregulated in GC cells. Furthermore, DDP enhanced the decrease in miR-4295 expression and the increase in LRIG1 expression in GC cells. miR-4295 promoted the proliferation and inhibited the DDP-induced apoptosis of GC cells without DDP treatment. In addition, miR-4295 increased the expression levels of EGFR, PI3K, Akt, p-PI3K and p-Akt, suggesting that miR-4295 promotes the activation of the EGFR/PI3K/Akt signaling pathway by targeting LRIG1. miR-4295 targeted and negatively regulated LRIG1 expression to activate the EGFR/PI3K/Akt signaling pathway, thereby promoting the proliferation of the GC cells and inhibiting the apoptosis of the GC cells induced by DDP. Therefore, miR-4295 may be a novel therapeutic target in patients with GC.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP115532520	Tetramethylrhodamine ethyl ester perchlorate		115532-52-0	Price

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