MiR-192-5p reverses cisplatin resistance by targeting ERCC3 and ERCC4 in SGC7901/DDP cells

Abstract

Cisplatin chemoresistance is a clinical obstacle in the treatment of gastric cancer (GC). Enhanced DNA repair capacity may lead to cisplatin resistance. However, the detailed molecular mechanism of GC cisplatin resistance specifically involving nucleotide excision repair (NER) is not clear. However, the mechanism through which the NER pathway contributes to cisplatin resistance in GC is still unclear. In light of the crucial role of microRNAs (miRNAs) in regulating protein expression and biological behavior, we aimed to analyze the expression and function of miR-192-5p in the NER pathway and its role in cisplatin resistance in GC. Comet assays were performed to measure the amount of DNA damage and repair in the SGC7901 and SGC7901/DDP GC cell lines by observing the tail length. MiRNA expression levels in SGC7901/DDP and SGC7901 cells were detected by microarray. Quantitative real-time PCR (qRT-PCR) was carried out to confirm the expression level of miR-192-5p. Lentiviral vector transfection modifies miR-192-5p levels in SGC7901/DDP and SGC7901 cells. The IC 50 values of cisplatin-treated cells were assessed by MTT assays. The protein level was determined by Western blot and immunohistochemistry. With enhanced DNA repair, the expression levels of ERCC3 and ERCC4 in SGC 7901DDP cells increased, while miR-192-5p was significantly downregulated in SGC7901/DDP compared with SGC7901 cells. ERCC3 and ERCC4 were identified as the main targets of miR-192-5p. Forced expression of miR-192-5p in SGC7901/DDP cells significantly inhibited the expression of ERCC3 and ERCC4, making GC cells more sensitive to cisplatin in vitro and in vivo. In contrast, knockdown of miR-192-5p expression in SGC7901 cells increased the expression of ERCC3 and ERCC4, resulting in cisplatin resistance in vitro and in vivo. MiR-192-5p partially reversed GC cisplatin resistance by targeting ERCC3 and ERCC4, which participate in the NER pathway, suggesting that miR-192-5p may be a potential biomarker and therapeutic target for GC cisplatin resistance.

miR-192-5p suppresses the progression of lung cancer bone metastasis by targeting TRIM44

“…Ectopic expression of miR-192 may be related to tumour occurrence as it exerts a significant effect on the progression of various malignancies. Recent studies have reported that miR-192 is considerably reduced in many malignant tumours and may be involved in regulating the proliferation, migration, and invasion of cancer cells in neoplasms 20,21,30,31 . For instance, Ji et al 30 suggested that miR-192-5p was significantly reduced in human bladder cancer.…”

“…In addition, many studies have already demonstrated that miRNA dysfunction is involved in the occurrence and progression of malignancies, such as breast cancer, gastric carcinoma, prostate cancer, and lung cancer [16][17][18][19] . In recent years, various studies have shown that miR-192-5p is significantly downregulated in malignant carcinoma, while miR-192-5p overexpression may play a potential role in suppressing tumourigenesis through different mechanisms 20,21 . In lung cancer bone metastasis, miR-192-5p plays a major role in inhibiting tumourigenesis 22,23 .…”

Noncoding RNAs in gastric cancer: implications for drug resistance

“…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].…”

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

“…Overexpression of miR-421, miR-320a, miR-192-5p, miR-181a, miR-148a-3p, miR-145 and miR-let-7b, and reduced expression of miR-135b-5p and miR-21-5p could enhance the chemosensitivity to DDP, which was observed in both GC cell lines and in animal tumor models. [23][24][25][26][27][28][29][30] These miRNAs could become more promising targets for further clinical research after resolving some key technical problems, such as selecting suitable carrier for mimics and inhibitors of miRNAs. Moreover, although miR-218, miR-200c, miR-198, miR34a, and miR-30a were only investigated in cell lines, each of these microRNAs was reported to be involved in DDP resistance in more than one separate study, [32][33][34][35][36][37][38][39][40] suggesting that they warrant further attention.…”