Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness

Pei Chi Hou, Yo Hua Li, Shih Chieh Lin, Shau Chieh Lin, Jenq Chang Lee, Bo Wen Lin, Jing Ping Liou, Jang Yang Chang, Ching Chuan Kuo, Yi Min Liu, H. Sunny Sun, Shaw Jenq Tsai

研究成果: Article同行評審

36 引文 斯高帕斯(Scopus)

摘要

Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2–derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2–induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens.

原文English
頁(從 - 到)4305-4316
頁數12
期刊Cancer Research
77
發行號16
DOIs
出版狀態Published - 2017 八月 15

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究

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