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Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells
Shih-Chieh Lin, … , Shao-Chieh Lin, Shaw-Jenq Tsai
Shih-Chieh Lin, … , Shao-Chieh Lin, Shaw-Jenq Tsai
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1905-1916. https://doi.org/10.1172/JCI44362.
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Research Article Oncology

Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells

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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

Shih-Chieh Lin, Chun-Wei Chien, Jenq-Chang Lee, Yi-Chun Yeh, Keng-Fu Hsu, Yen-Yu Lai, Shao-Chieh Lin, Shaw-Jenq Tsai

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Figure 1

DUSP2 is downregulated in most cancer cells.

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DUSP2 is downregulated in most cancer cells.
(A) Levels of DUSP2 mRNA qu...
(A) Levels of DUSP2 mRNA quantified by RT-qPCR in cDNA panels of several cancer tissues and their normal counterparts. *P < 0.05 compared with normal. (B) Representative immunohistochemical staining for DUSP2 (left panels; and at higher magnification in middle panels) and CAIX (right panels) in paired normal and cancerous cervical (Cx Ca) tissues. Scale bars: 200 μm and 25 μm for low and high magnification, respectively. (C) Accumulated percentage of DUSP2 staining intensity in normal (N) and cancerous (Ca) cervical tissues. (D) Representative immunohistochemical staining for DUSP2 and CAIX in paired normal and colon cancer (Col Ca) tissues. Scale bars: 25 μm. (E) Accumulated percentage of DUSP2 staining intensity in normal and cancerous colorectal (colon) tissues. (F) Accumulated percentage of DUSP2 staining intensity in paired normal and cancerous tissues grouped by pathological stages. N > Ca, expression level is greater in normal tissue than in cancer; N = Ca, expression level is equal in normal tissue and cancer; N < Ca, expression level is lower in normal tissue than in cancer.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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