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

• Published in: Cancer science Vol. 110; no. 2; pp. 662 - 673
• Main Authors: Lee, So D., Yu, Dayeon, Lee, Do Y., Shin, Hyun‐Soo, Jo, Jeong‐Hyeon, Lee, Yong C.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01-02-2019
• Subjects: apoptosis; Apoptosis - genetics; cancer; CD44(+) cell; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; cisplatin; Cisplatin - pharmacology; Down-Regulation - genetics; Gene Expression Regulation, Neoplastic - genetics; Humans; Hyaluronan Receptors - genetics; MicroRNAs - genetics; miR‐193a‐3p; Original; Proto-Oncogene Proteins c-bcl-2 - genetics; Serine-Arginine Splicing Factors - genetics; Signal Transduction - genetics; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; apoptosis; cancer; cisplatin; miR-193a-3p; CD44(+) cell
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13894

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.
The present study suggests that upregulation of miR‐193a‐3p can inhibit cisplatin‐induced mitochondrial apoptosis in CD44(+) gastric cancer cells. Thus, regulating miR‐193a‐3p might be an attractive treatment strategy to target cisplatin‐resistant cells in gastric cancer.