title: Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells.
abstract: Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chien
authors.forename: Jenq-Chang
authors.initials: JC
authors.lastname: Lee
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Yeh
authors.forename: Keng-Fu
authors.initials: KF
authors.lastname: Hsu
authors.forename: Yen-Yu
authors.initials: YY
authors.lastname: Lai
authors.forename: Shao-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Shaw-Jenq
authors.initials: SJ
authors.lastname: Tsai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D054641:Dual Specificity Phosphatase 2 / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic
chemical_list: D051793:Hypoxia-Inducible Factor 1; D054641:Dual Specificity Phosphatase 2