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微小RNA-193a-5p通过SRSF6介导的OGDHL和ECM1可变剪接促进胰腺癌细胞转移。

miR-193a-5p promotes pancreatic cancer cell metastasis through SRSF6-mediated alternative splicing of OGDHL and ECM1.

作者信息

Li Manman, Wu Pandi, Yang Zhaocong, Deng Siwei, Ni Lingyu, Zhang Yanfeng, Jin Liang, Pan Yi

机构信息

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University 24 Tongjiaxiang Avenue, Nanjing, Jiangsu, PR China.

Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University Nanjing 21008, PR China.

出版信息

Am J Cancer Res. 2020 Jan 1;10(1):38-59. eCollection 2020.

Abstract

MicroRNAs (miRNAs) are short and non-coding RNAs binding to 3'UTR of target mRNAs to downregulate their expression. Recent studies have shown that miRNAs indirectly regulated alternative splicing (AS) by targeting splicing factors and caused shifts in splicing patterns of target genes. However, the roles of miRNA-regulating splicing factors in pancreatic cancer progression remain unknown. Herein, we reported that miR-193a-5p was markedly upregulated in pancreatic cancer tissues and cells and correlated with clinical outcomes of pancreatic cancer patients. Overexpression of miR-193a-5p contributed to the metastasis of pancreatic cancer cells both and . The mechanistic investigation suggested that miR-193a-5p modulated oxoglutarate dehydrogenase-like (OGDHL) and extracellular matrix protein 1 (ECM1) AS by targeting serine/arginine-rich splicing factor 6 (SRSF6), leading to the activation of the epithelial-to-mesenchymal transition (EMT) process. Together, our findings highlighted the role of miR-193a-5p-targeting SRSF6 in pancreatic cancer metastasis, which may serve as a novel target for pancreatic cancer diagnosis and therapy.

摘要

微小RNA(miRNA)是一类短链非编码RNA,可与靶标mRNA的3'非翻译区(3'UTR)结合,从而下调其表达。最近的研究表明,miRNA可通过靶向剪接因子间接调控可变剪接(AS),并导致靶标基因剪接模式的改变。然而,miRNA调控的剪接因子在胰腺癌进展中的作用仍不清楚。在此,我们报道miR-193a-5p在胰腺癌组织和细胞中显著上调,且与胰腺癌患者的临床预后相关。miR-193a-5p的过表达促进了胰腺癌细胞的转移。机制研究表明,miR-193a-5p通过靶向富含丝氨酸/精氨酸的剪接因子6(SRSF6)调节α-酮戊二酸脱氢酶样蛋白(OGDHL)和细胞外基质蛋白1(ECM1)的可变剪接,从而导致上皮-间质转化(EMT)过程的激活。总之,我们的研究结果突出了miR-193a-5p靶向SRSF6在胰腺癌转移中的作用,这可能为胰腺癌的诊断和治疗提供一个新的靶点。

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