miR‑138‑5p modulates the expression of excision repair cross‑complementing proteins ERCC1 and ERCC4, and regulates the sensitivity of gastric cancer cells to cisplatin

Abstract

The microRNA (miR)-138-5p affects the chemotherapeutic sensitivity of several human cancer types. In the present study, the expression and regulatory mechanisms of miR-138-5p were investigated in the gastric cancer cell line SGC7901 and its cisplatin-resistant derivative SGC7901/DDP. Gene microarray and reverse transcription-quantitative polymerase chain reaction analyses revealed that miR-138-5p was expressed at significantly lower levels in SGC7901/DDP compared with SGC7901 cells. Using computational predictive algorithms, two proteins involved in the nuclear excision repair pathway were identified, excision repair cross-complementing (ERCC)1 and ERCC4, as putative miR-138-5p target genes. Western blot analysis confirmed that ERCC1 and ERCC4 expression levels were inversely proportional to miR-138-5p levels in SGC7901 and SGC7901/DDP cells. Furthermore, ERCC1 and ERCC4 were upregulated in SGC7901 cells expressing miR-138-5p-targeting short hairpin RNA and, conversely, downregulated in SGC7901/DDP cells overexpressing miR-138-5p, confirming that this miRNA regulates ERCC protein levels. Notably, miR-138-5p silencing enhanced the cisplatin resistance of SGC7901 cells, while miR-138-5p overexpression partially reversed the cisplatin resistance of SGC7901/DDP cells. Taken together, these data suggest that miR-138-5p regulates the sensitivity of gastric cancer cells to cisplatin, possibly by modulating expression of the DNA repair proteins ERCC1 and ERCC4.

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

“…The excision repair cross-complementation group (ERCC) is known to participate in the nucleotide excision repair (NER) pathway [57]. Recent evidence suggested that miR-138-5p reverses drug resistance in gastric cancer cells as a result of targeting ERCC1 and ERCC4 genes [58] (Table 2). Additionally, several studies demonstrated that miR-138-5p is a tumor suppressor and suppresses the growth and metastasis of cancer cells [59,60].…”

Noncoding RNAs in gastric cancer: implications for drug resistance

“…MiRNAs are a class of sncRNAs of 19-24 nt in length, which could post-transcriptionally suppress gene expression via binding to the 3'-untranslated region (3'-UTR) of multiple target messenger RNAs (mRNAs) and/or other RNAs [42,43]. Multiple miRNAs are dysregulated in gastric cancer and play a crucial role in tumorigenesis, cancer metastasis, as well as development of resistance to drugs and radiation [44][45][46][47][48]. It has been observed that significantly changed miRNA expression profiles in drug-resistant gastric cancer cells compared to those in drug-sensitive cells.…”

“…Similarly, tumor suppressor miR-362-5p, miR-198, miR-574-3p, miR-876-3p, miR-874 and let-7b have been reported to reverse DDP resistance of gastric cancer cells via silencing suppressor of zeste 12 protein (SUZ12), fibroblast growth factor receptor 1 (FGFR1), zinc finger E-box binding homeobox transcription factor 1 (ZEB1), TMED3, autophagy-related 16-like 1 (ATG16 L1) and AURKB, respectively [117][118][119][120][121][122]. In addition, via targeting excision repair cross-complementing (ERCC), exogenous over-expression of tumor suppressor miR-122, miR-138-5p and miR-192-5p could also reverse DDP resistance of gastric cancer [48,123,124].…”

Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma

“…In GAC, changes in ERCC1 expression have been associated with miR-122 and miR-139-5p, whose expression is reduced in cisplatin-resistant cells and inversely correlated with that of ERCC1. When both miRNAs were induced in vitro, ERCC1 protein levels decreased, and the sensitivity to cisplatin was restored [90,91].…”

“…ERCC4 (or XPF), which forms a heterodimer with ERCC1 to repair DNA, has also been associated with GAC chemoresistance. In vitro studies have suggested that ERCC4 expression could be modulated by several miRNAs, inducing cisplatin resistance in GAC cells [91,99]. However, the few clinical studies performed up to date have not found a link between ERCC4 expression [45] or its genetic variants [104] with the sensitivity to platinum-containing drugs.…”