Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway

Abstract

Gastric cancer (GC) has been classified as the fourth leading cause of cancer‐related deaths worldwide. Due to their ability to suppress the expression of target genes, microRNAs (miRNAs) are listed as one of the key elements involved in the formation and development of tumors. This study was therefore conducted to investigate the effects of microRNA‐135b (miR‐135b) on cisplatin [ds‐diamminedichloroplatinum (CDDP)] resistance of GC cells through the MAPK signaling pathway by targeting mammalian ste20‐like kinase 1 (MST1). A microarray‐based gene expression analysis was performed to screen the GC‐related differentially expressed genes. The 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide assay was performed to determine the sensitivity of GC cells to CDDP. The bioinformatics database and dual lucif erase reporter gene assay were used to check whether MST1 was a direct target gene of miR‐135b. GC cell lines were prepared with high CDDP resistance, after which they were cultured and transfected respectively, followed by the administration of transfected cells into nude mice and subsequent treatment with CDDP in an attempt to identify the underlying mechanisms and functions of miR‐135b in relation to MST1 in GC progression. The results were highly indicative of the crucial role played by MST1 in the development of GC and the sensitivity of GC to CDDP. miR‐135b was found to regulate MST1, which in turn had an impact on the development of GC. MKN28 was observed to be most sensitive to CDDP, whereas MKN45 presented with the poorest sensitivity to CDDP. Furthermore, the down‐regulation of miR‐135b resulted in inactivation of the MAPK signaling pathway; increased the expression of MST1 and Bax; and decreased expression of p‐p38MAPK, p‐ERKl/2, P‐glycoprotein, p38MAPK, ERK1/2, multidrug resistance protein 1, multidrug resistance‐associated protein 1, lung resistance‐related protein, and Bcl‐2, thus inhibiting CDDP resistance of GC cells. The down‐regulation of miR‐135b also restrained cell proliferation and induced the apoptosis rate of GC cells. In summary, the results of this study showed that the down‐regulation of miR‐135b induced apoptosis, and it inhibited proliferation and CDDP resistance of GC cells by inactivating the MAPK signaling pathway and increasing the expression of MST1.—Zhou, J., Chen, Q. Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway. FASEB J. 33, 3420–3436 (2019). http://www.fasebj.org

Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer

“…In non-small cell lung cancer, amplification of miR-135b suppressed the chemoresistance of cancer cells to cisplatin treatment by downregulating Frizzled-1 (55). However, opposite effects of miR-135b-5p in certain cancers have also been reported (56,57). This could be partially explained by the mechanism by which miRNA binding to mRNAs is often achieved with imperfect complementarity, and its targets varied in different cellular contexts and tumor types.…”

Noncoding RNAs in gastric cancer: implications for drug resistance

“…MiR-421, a highly expressed miRNA in advanced gastric cancer patients, could also promote gastric cancer metastasis and DDP resistance through inhibiting E-cadherin and caspase-3 expression, in vivo and in vitro [91]. In addition, oncogenic miR-135b-5p, miR-135b, miR-17-5p, miR-193a-3p, miR-4295 and miR-3174 confer DDP resistance of gastric cancer cells through silencing Krüppel-like factor 4 (KLF4), mammalian ste20-like kinase 1 (MST1), p21, SRSF2, leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) and ARHGAP10, respectively [28,[92][93][94][95][96]. For oxaliplatin resistance, the oncogenic miR-27a has been found to enhance MDR properties by inducing MDR1/P-gp, lung resistance protein (LRP) and Bcl-2 expression in gastric cancer [97].…”

<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.…”

“…The miRNAs reported to be involved in the mechanism of DDP resistance mainly influence the phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) signaling pathway. 29,30,38,39,[41][42][43][44][45][46][47][48][49] However, different miRNAs may have opposite effects on the same pathway. For example, miR-206 targets MAPK to enhance the chemosensitivity to DDP, and miR-135b-5p targets mammalian ste20-like kinase 1 (MST1) through the MAPK signaling pathway to induce drug resistance.…”

“…For example, miR-206 targets MAPK to enhance the chemosensitivity to DDP, and miR-135b-5p targets mammalian ste20-like kinase 1 (MST1) through the MAPK signaling pathway to induce drug resistance. 29,43 Thus, it may be necessary to consider the antagonistic effects of different miRNAs in reversing drug resistance in future studies. In addition, some genes were identified to be targets of more than one miRNA, such as survivin (miR-218, miR-34a), PTEN (miR-106a, miR-21-5p), P-glycoprotein (P-gp) (miR-129, miR-30a), and insulinlike growth factor 1 receptor (IGF1R) (miR-1271, miR-143).…”