Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Cancer Sci. 2019 Feb;110(2):662-673. doi: 10.1111/cas.13894. Epub 2018 Dec 26.
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.
顺铂是一种广泛用于治疗各种癌症的抗癌药物。然而，顺铂耐药性的发展已经阻碍了这种药物在癌症治疗中的效率。众所周知，化疗耐药性的发展涉及许多信号通路。最近，人们的注意力集中在 microRNAs (miRNAs) 作为化疗耐药性发展的潜在重要上游调节剂上。CD44 是胃癌干细胞标志物之一，在自我更新、肿瘤起始、转移和化疗耐药性的调节中发挥作用。本研究旨在探讨 miRNA 介导的顺铂耐药性在 CD44 阳性胃癌干细胞中的机制。我们通过 FACS 根据 CD44 表达水平对胃癌细胞进行分选，并通过微阵列分析分析它们的 miRNA 表达谱。我们发现 miR-193a-3p 在 CD44(+)细胞中明显上调与 CD44(-)细胞相比。此外，miR-193a-3p 靶基因 SRSF2 在 CD44(+)细胞中下调。我们研究了 SRSF2 对 Bcl-X 和 caspase 9 mRNA 剪接的调节作用，发现这些基因产生了更多的促凋亡变体。我们还发现，与 CD44(-)细胞相比，CD44(+)细胞中下调了下游抗凋亡基因如 Bcl-2，而上调了促凋亡基因如 Bax 和细胞色素 C。此外，我们发现高水平的 miR-193a-3p 触发了 CD44(+)细胞中顺铂耐药性的发展。在 CD44(+)细胞中抑制 miR-193a-3p 增加了 SRSF2 的表达，并改变了多个凋亡基因的水平。此外，抑制 miR-193a-3p 降低了细胞活力并增加了凋亡细胞的数量。因此，miR-193a-3p 可能通过调节线粒体凋亡途径参与顺铂耐药性的发展。miR-193a-3p 可能成为顺铂耐药性胃癌治疗的有前途的靶点。
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