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Critical Roles of CD151-alpha6beta1 and CD151-alpha6beta4 Integrin Complexes in Human Ovarian Cancer

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Final rept. 1 Jul 2008-30 Jun 2009

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The oncogenic ErbB receptors, EGFR and ErbB2, are tightly coupled with the malignancy of human ovarian carcinomas. The inhibitors that target these oncogenes, however, have received limited consideration in the treatment of this type of human cancer. To a large extent, this is due to the limited sensitivity or susceptibility of ovarian cancer cells to these therapeutic agents. Recently, it has been reported that laminin-binding LB integrins alpha6beta1 and alpha6beta4 act in synergy with both EGFR and ErbB2 in human epithelia-origin cancer. This suggests that targeting LB integrins may potentially provide a novel avenue to enhance the efficacy of these ErbB inhibitors in treating human ovarian cancer. CD151, a newly discovered functional regulator of laminin-binding integrins, has also been implicated in the malignancy of several types of human cancer. We have investigated the possibility that disrupting CD151-alpha6beta1 and CD151-alpha6beta4 molecular complexes would enhance the response of human ovarian cancer cells to ErbB receptor-based therapeutic inhibitors. This was achieved by disrupting CD151-dot6beta1 and CD151-alpha6beta4 complexes through the stable expression of CD151-specific RNA interference and evaluating the subsequent impact on malignant ovarian cancer cell behaviors, proliferation, and response to ErbB inhibitors. Upon the disruption of CD151-LB integrin complexes, there was a marked decrease in cell invasion through matrigel for a number of human ovarian cancer cell lines. In certain ovarian cancer cell lines, CD151 ablation also led to a significant inhibition of the synergy between ErbB receptors and integrin complexes as well as an increase in the sensitivity of ovarian cancer cells to ErbB inhibitors. Surprisingly, CD151 ablation appeared to affect the morphology of some ovarian cancer cell lines, leading to the dramatic change from an epithelial-like to a mesenchymal-like phenotype.

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  • Biochemistry
  • Medicine and Medical Research

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