MicroRNA-500 sustains nuclear factor-κB activation and induces gastric cancer cell proliferation and resistance to apoptosis
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Liang Zhang1,*, Ya Ding2,*, Zhongyu Yuan3, Junling Liu3, Jian Sun4, Fangyong Lei5, Shu Wu5, Su Li4, Dongsheng Zhang3
1State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Department of Diagnostic Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
2Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
3Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
4Clinical Trial Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
5Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
*These authors have contributed equally to this work
Dongsheng Zhang, e-mail: firstname.lastname@example.org
Keywords: miR-500, Gastric cancer, NF-κB signalling pathway, deubiquitinase
Received: August 02, 2014 Accepted: November 20, 2014 Published: January 30, 2015
Ubiquitin deconjugation of key signalling molecules by deubiquitinases (DUBs) such as cylindromatosis (CYLD), A20, and OTU deubiquitinase 7B (OTUD7B) has emerged as an important regulatory mechanism in the downregulation of NF-κB signalling and homeostasis. However, how these serial negative regulations are simultaneously disrupted to result in constitutive activation of NF-κB signalling in cancers remains puzzling. Here, we report that the miR-500 directly repressed the expression of CYLD, OTUD7B, and the A20 complex component Tax1-binding protein 1 (TAX1BP1), leading to ubiquitin conjugation of receptor-interacting protein 1 (RIP1) and sustained NF-ĸB activation. Furthermore, we found that miR-500 promoted gastric cancer cell proliferation, survival, and tumorigenicity. Importantly, miR-500 was upregulated in gastric cancer and was highly correlated with malignant progression and poor survival. Hence, we report the uncovering of a novel mechanism for constitutive NF-κB activation, indicating the potentially pivotal role of miR-500 in the progression of gastric cancer.
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