Korourian Alireza, Roudi Raheleh, Shariftabrizi Ahmad, Madjd Zahra
1 Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14496-14530, Iran.
2 Oncopathology Research Center, Iran University of Medical Sciences, Tehran 14496-14530, Iran.
Exp Biol Med (Maywood). 2017 Dec;242(18):1842-1847. doi: 10.1177/1535370217728460. Epub 2017 Aug 24.
microRNAs are small single-stranded non-coding RNA molecules which modify gene expression by silencing potential target genes. The aberrant expression of RhoA, a small GTPase protein of Rho family, is involved in gastric cancer tumorigenesis. Since miR-31 is a pleomorphic molecule, we evaluated the miR-31/RhoA axis in inducing the malignant phenotype of gastric cancer cells MKN-45. Also, the clinicopathological significance of RhoA was investigated in a well-defined collection of gastric carcinomas which were embedded in tissue microarray blocks. Induction of miR-31 in MKN-45 followed by suppression of RhoA expression resulted in increased sensitivity to 5-fluorouracil, inhibition of cell proliferation, and invasion compared to the control groups. Immunohistochemical analysis in gastric adenocarcinoma patients' samples showed significantly higher expression of RhoA in diffuse versus intestinal subtype tumors ( P = 0.009), poorly differentiated versus well and moderately differentiated tumors ( P = 0.03) and the presence of vascular invasion versus the absence of vascular invasion ( P = 0.04). Our findings suggest a critical role for miR-31, as a tumor suppressor gene, in gastric cancer tumorigenesis by targeting the RhoA. Impact statement Gastric cancer ranks as the third leading cause of cancer-associated deaths worldwide. The RhoA gene encodes a small GTPase protein of Rho family (RhoA) that its dysregulation is associated with cell motility and invasion. A strong line of evidence supports the regulation of RhoA by a number of miRs, including miR-31 in tumors. Our findings revealed that miR-31 is involved in gastric cancer tumorigenesis as a tumor suppressor gene. Through down-regulation of RhoA, miR-31 decreased cell proliferation, migration, and invasion in gastric cancer cells. In addition, induction of miR-31 increased sensitivity to 5-FU; thus, increasing its tissue concentrations could be a potential target for treatment of gastric cancer in the future.
微小RNA是一类小的单链非编码RNA分子，可通过使潜在靶基因沉默来修饰基因表达。RhoA是Rho家族的一种小GTPase蛋白，其异常表达与胃癌的发生有关。由于miR-31是一种多形性分子，我们评估了miR-31/RhoA轴在诱导胃癌细胞MKN-45恶性表型中的作用。此外，还在组织微阵列块中包埋的一组明确的胃癌样本中研究了RhoA的临床病理意义。与对照组相比，MKN-45细胞中miR-31的诱导随后RhoA表达的抑制导致对5-氟尿嘧啶的敏感性增加、细胞增殖和侵袭受到抑制。对胃腺癌患者样本的免疫组织化学分析显示，弥漫型肿瘤与肠型肿瘤相比，RhoA表达显著更高（P = 0.009），低分化肿瘤与高分化和中分化肿瘤相比（P = 0.03），以及存在血管侵犯与无血管侵犯相比（P = 0.04）。我们的研究结果表明，作为一种肿瘤抑制基因，miR-31通过靶向RhoA在胃癌发生中起关键作用。影响声明 胃癌是全球癌症相关死亡的第三大主要原因。RhoA基因编码Rho家族的一种小GTPase蛋白（RhoA），其失调与细胞运动和侵袭有关。大量证据支持多种微小RNA对RhoA的调控，包括肿瘤中的miR-31。我们的研究结果表明，miR-31作为一种肿瘤抑制基因参与胃癌的发生。通过下调RhoA，miR-31降低了胃癌细胞的增殖、迁移和侵袭。此外，miR-31的诱导增加了对5-FU的敏感性；因此，提高其组织浓度可能是未来治疗胃癌的一个潜在靶点。
