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.

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The crosstalk between RON and MET in colorectal cancer seems important. Evaluating the expression patterns of RON and MET was predictive of clinical outcome for patients with colorectal cancer.

Purpose: The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells; however, how cancer cells accomplish this process remains unclear. Thus, we aimed to investigate the underlying mechanism that controls the early event of metastasis. Experimental Design: One hundred and thirty-seven paired colorectal carcinoma and normal colon tissues were examined by immunohistochemical staining and Western blot for the expression of CD151, a member of the tetraspanin family that plays important roles in cell adhesion and motility. The effect of CD151 on cancer cell adhesion was investigated under normoxia and hypoxia conditions. Results: The level of CD151 was down-regulated in colon cancer compared with the paired normal counterparts. Expression of CD151was negatively regulated by hypoxia inducible factor1^dependent hypoxic stress. Suppression of CD151by hypoxia caused the detachment of cancer cells from the surrounding matrix and neighboring cells whereas restoration of CD151expression during reoxygenation facilitated the adhesion capacity. Clinical examination further showed that metastasized cancer cells expressed a greater level of CD151 compared with that of primary tumor. Conclusion: Regulation of CD151 by oxygen tension may play an important role in cancer metastasis by regulating the detachment from the primary site and homing in the secondary site.Cancer metastasis is a complex, multistep process with mechanisms largely unknown despite intensive investigation in the past. The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells. Adhesions between normal epithelial cells and cell-matrix are strong so local cell invasion is not able to occur. Therefore, the necessary early event in cancer invasion and metastasis is the conversion of the stationary phenotype to the migratory phenotype. This can be achieved by down-regulation of cell adhesion molecules such as cadherins and integrins. Indeed, studies have revealed that loss or down-regulation of E-cadherin and one or more of the integrins is a common feature of several epithelial malignancies (1, 2). Nonetheless, the underlying mechanisms of causing the down-regulation of these molecules are not yet clear. In addition, whether there are other molecules that also control cancer cell adhesion needs to be elucidated.Many factors have been identified as playing important roles in the regulation of cancer metastasis. Among these, hypoxia is the most common and critical one. Because oxygen can only diffuse for 150 to 200 Am, cells will face the hypoxic stress when distances of cells from a capillary exceed this range. Owing to the rapid growing nature, cancer cells of solid tumors frequently encounter reduced oxygen tension. The hypoxic stress will force cancer cells to develop necessary processes such as induction of angiogenesis, metabolic switch, and migration to avoid cell death. These responses to hypoxia are mainly mediated through genes regulated by t...