Upregulated microRNA‐193a‐3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells

Abstract

Cisplatin is a well‐known anticancer drug used to treat various cancers. However, development of cisplatin resistance has hindered the efficiency of this drug in cancer treatment. Development of chemoresistance is known to involve many signaling pathways. Recent attention has focused on microRNAs (miRNAs) as potentially important upstream regulators in the development of chemoresistance. CD44 is one of the gastric cancer stem cell markers and plays a role in regulating self‐renewal, tumor initiation, metastasis and chemoresistance. The purpose of the present study was to examine the mechanism of miRNA‐mediated chemoresistance to cisplatin in CD44‐positive gastric cancer stem cells. We sorted gastric cancer cells according to level of CD44 expression by FACS and analyzed their miRNA expression profiles by microarray analysis. We found that miR‐193a‐3p was significantly upregulated in CD44(+) cells compared with CD44(−) cells. Moreover, SRSF2 of miR‐193a‐3p target gene was downregulated in CD44(+) cells. We studied the modulation of Bcl‐X and caspase 9 mRNA splicing by SRSF2 and found that more pro‐apoptotic variants of these genes were generated. We also found that downstream anti‐apoptotic genes such as Bcl‐2 were upregulated, whereas pro‐apoptotic genes such as Bax and cytochrome C were downregulated in CD44(+) cells compared to CD44(−) cells. In addition, we found that an elevated level of miR‐193a‐3p triggered the development of cisplatin resistance in CD44(+) cells. Inhibition of miR‐193a‐3p in CD44(+) cells increased SRSF2 expression and also altered the levels of multiple apoptotic genes. Furthermore, inhibition of miR‐193a‐3p reduced cell viability and increased the number of apoptotic cells. Therefore, miR‐193a‐3p may be implicated in the development of cisplatin resistance through regulation of the mitochondrial apoptosis pathway. miR‐193a‐3p could be a promising target for cancer therapy in cisplatin‐resistant gastric cancer.

miR‐451a inhibits cancer growth, epithelial‐mesenchymal transition and induces apoptosis in papillary thyroid cancer by targeting PSMB8

“…microRNAs (miRNAs) belong to small noncoding RNAs which regulate the expression of their target genes at the post-transcription level. 7 miRNAs bind to the seed sequences of the 3'-untranslated region of their target messenger RNAs (mRNAs) and mediate the degradation of corresponding mRNAs or inhibit their translation. 8 Multiple studies have reported the correlation between aberrant expression of miRNAs and cancer progression.…”

miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2

“…miRNA dysregulation has been reported to be valuable for GC diagnosis [30][31][32]. Recently, several studies even demonstrated the potential of miRNA in GC diagnosis and treatment [33,34]. Here, we proposed that up-regulation of miR-100-3p could inhibit proliferation and enhance apoptosis of GC cells.…”

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].…”

“…Multiple ncRNAs acts as oncogenes or tumor suppressor genes during carcinogenesis and can also serve as diagnostic and prognostic markers of cancer patients after certain therapies [21,22]. In gastric cancer, a variety of abnormally expressed ncRNAs were identified to promote tumor progression, radioresistance, chemoresistance and targeted therapy sensitivity [23][24][25][26][27][28]. Interestingly, several miRNAs, lncRNAs and circRNAs have been found to play an essential part in gastric cancer drug resistance, especially in chemoresistance.…”