MicroRNA-500 sustains nuclear factor-κB activation and induces gastric cancer cell proliferation and resistance to apoptosis

Liang Zhang; Ya Ding; Zhongyu Yuan; Junling Liu; Jian Sun; Fangyong Lei; Shu Wu; Su Li; Dongsheng Zhang

doi:10.18632/oncotarget.2800

MicroRNA-500 sustains nuclear factor-κB activation and induces gastric cancer cell proliferation and resistance to apoptosis

Oncotarget. 2015 Feb 10;6(4):2483-95. doi: 10.18632/oncotarget.2800.

Authors

Liang Zhang¹, Ya Ding², Zhongyu Yuan³, Junling Liu³, Jian Sun⁴, Fangyong Lei⁵, Shu Wu⁵, Su Li⁴, Dongsheng Zhang³

Affiliations

¹ State 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.
² Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
³ Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
⁴ Clinical Trial Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
⁵ Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.

Abstract

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-Ä¸B 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Animals
Apoptosis / genetics*
Blotting, Western
Cell Line, Tumor
Cell Proliferation / genetics*
Cells, Cultured
Deubiquitinating Enzyme CYLD
Disease Progression
Endopeptidases / genetics
Endopeptidases / metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mice, Nude
MicroRNAs / genetics*
Middle Aged
NF-kappa B / metabolism*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Stomach Neoplasms / genetics*
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology
Survival Analysis
Transplantation, Heterologous
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

3' Untranslated Regions
Intracellular Signaling Peptides and Proteins
MIRN500 microRNA, human
MicroRNAs
NF-kappa B
Neoplasm Proteins
TAX1BP1 protein, human
Tumor Suppressor Proteins
Endopeptidases
OTUD7B protein, human
CYLD protein, human
Deubiquitinating Enzyme CYLD