Loss Of Dab2ip Promotes Colorectal Cancer Progression By Inducing Epithelial-Mesenchymal Transition And Cancer Stem-Like Cell Signatures

CANCER RESEARCH(2012)

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摘要
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer-related death in the United States. Approximately 50% of patients diagnosed with CRC will die because of tumor recurrence and distant metastases. The aberrant activation of epithelial-mesenchymal transition (EMT) is known to play a critical role in triggering malignant tumor progression not only in tumor metastasis but also in tumor recurrence. Moreover, EMT is believed to promote the onset of cancer stem cell (CSC). Unveiling the genes regulating CRC EMT and cell stemness should lead to novel therapeutic approaches. Previously, we reported that DAB2IP, a novel member of the Ras GTPase-activating protein family, functions a scaffold protein to balance proliferation and apoptosis in prostate cancer cells. DAB2IP is down-regulated in various human cancers and functions as a bona fide tumor suppressor in cancer development; however, in CRC, the role and mechanism of DAB2IP contributes to EMT and CSC has not been elucidated. In this study, firstly, we examined the expression of the DAB2IP in clinical colorectal neoplasms (N=162 patients) using immunohistochemistry. The clinicopathologic (age, sex, tumor site, and grade) factors were also examined. Our data showed that DAB2IP expression levels were down-regulated in CRC tissues and lymphatic metastasis tissues (p<0.01). Loss of DAB2IP expression was correlated with tumor differentiation (p=0.004), distal metastasis (p=0.034) and Duke's stage (p<0.01). Multivariate analyses indicated that DAB2IP expression level was an independently prognostic marker for survival of patients with CRC (p<0.05). Patients with lower expression of DAB2IP had worse overall survival than higher expression of DAB2IP (p<0.01). Then, we determined the biological function of DAB2IP by knocking down endogenous DAB2IP protein in cultured CRC cells. Our results showed that loss of DAB2IP in CRC elicits EMT phenotype as demonstrated by morphological transformation, down-regulation of epithelial markers (e.g., E-cadherin) and upregulation of mesenchymal markers (e.g., vimentin). Moreover, loss of DAB2IP enhances the migration and colony-forming abilities of CRC cells in vitro and promotes tumor growth in vivo. Furthermore, knocking down endogenous DAB2IP in CRC cells increases the number of CD44high/Epcamhigh stem-like cell sub-populations, promotes the expression of stem cell markers and enhances the self-renewal capabilities of stem-like cells (sphere formation). In addition, DAB2IP could prevent translocation of hypoxia-inducible factor-1 (HIF-1) into nucleus and suppress its target genes (e.g., Twist, Snail) transcription. Taken together, our data provides strong evidence that loss of DAB2IP may contribute to CRC progression by activating EMT and enhancing the self-renewal of CSCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 341. doi:1538-7445.AM2012-341
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关键词
colorectal cancer progression,colorectal cancer,dab2ip,cancer progression,epithelial-mesenchymal,stem-like
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