miR-494 Sensitizes Gastric Cancer Cells to TRAIL Treatment Through Downregulation of Survivin

Abstract

Background/Aims: TNF-related apoptosis-inducing ligand (TRAIL) is a novel and low-toxic anti-tumor drug used for various cancers. However, cancer cells usually develop mechanisms to acquire the resistance against TRAIL. Among these changes, dysregulation of microRNAs (miRNAs) usually occurs in cancer cells and is responsible for induction of drug resistance. Methods: Expression of miR-494 in gastric cancer tissues and cell lines was detected by quantitative reverse transcriptase real time PCR (qRT-PCR) analysis. Effect of miR-494 on regulating the TRAIL sensitivity to gastric cancer cell lines was evaluated by MTT assays. Bioinformatics and luciferase reporter assays were used to confirm the regulation of miR-494 on survivin. Mitochondrial apoptosis pathway in gastric cancer cells was tested by western blot and flow cytometry analysis. Results: Obvious downregulation of miR-494 was observed in gastric cancer cells. Furthermore, we found that expression profile of miR-494 was associated with TRAIL-sensitivity in gastric cancer. Enforced expression of miR-494 was found to sensitize the gastric cancer cells to TRAIL-induced cytotoxicity. Mechanically, Luciferase reporter assays proved that survivin was the target of miR-494 in gastric cancer cells. Enforced expression of miR-494 decreased the expression of survivin, and thus promoted the TRAIL-induced mitochondria collapse and apoptosis pathway. Conclusion: MiR-494/survivin axis represents a potential mechanism which is responsible for TRAIL resistance in gastric cancer cells. Increasing the miR-494 expression may serve as a novel therapeutic strategy to sensitize gastric cancer cells to TRAIL treatment.

<p>miR-596 suppresses the expression of Survivin and enhances the sensitivity of osteosarcoma cells to the molecular targeting agent anlotinib</p>

“…Besides miR-596, microRNA-330-5p, microRNA-218, miR-542-3p, or miR-494 could also target Survivin and inhibit the proliferation or metastasis in some other cancers, such as gastric cancer. [65][66][67][68] It is valuable to examine the expression of the miRs in clinical tissues. TCGA is a common database; however, there are no data about Survivin-OSA in TCGA.…”

Recent advances of miRNAs in the development and clinical application of gastric cancer

“…The over-expression of miR-494 decreased survivin levels and established an axis for a potential mechanism to promote TRAIL-induced mitochondrial collapse and apoptosis pathway. [ 90 ] Notably, Wei et al [ 91 ] found that a well-known neurotransmitter related to stress, isoproterenol, also led to chemo-resistance in GC cells, and transfection with miR-373 inhibited the effects of isoproterenol on drug sensitivity. Interestingly, different non-coding RNAs, such as miRNAs, lncRNAs, and circRNAs, are critically involved in GC drug-resistant phenotype development.…”

<p>Research Progress in microRNA-Based Therapy for Gastric Cancer</p>

“…Some miRNAs, such as miR-4670-5p, miR-940, miR-493, miR-30e, and miR-7, have been shown to have antitumor effects both in vitro and in vivo, [99][100][101][102] and other miRNAs, such as miR-494, miR-124, miR-34a, miR-21, and miR-9, have been investigated in more than one study. [97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114]…”