Preclinical investigation demonstrates that Notch3 promotes anoikis resistance through COL4A2 upregulation in epithelial ovarian cancer, suggesting type IV collagen as a therapeutic target.
UNLABELLED: Ovarian cancer is a lethal disease with the majority of diagnosed women having distant metastases. Interestingly, although Notch3 overexpression has been correlated with poor survival in epithelial ovarian cancer (EOC), little is known about its mechanism of action. Data show that Notch3 specifically promotes anoikis resistance. In addition, data indicate a positive role for focal adhesion kinase (FAK) as well as downstream signaling kinases such as Akt and Erk 1/2 in promoting anchorage-independent growth. Mechanistically, both mRNA transcript and protein levels of type IV collagen (COL4A2) are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation reverses the anoikis sensitivity. Reduction of COL4A2 expression by RNAI-mediated knockdown induces cell death. Finally, elevated Notch3 expression levels correlate with higher COL4A2 expression in human ovarian tumor specimens. IMPLICATIONS: These data highlight type IV collagen as a novel therapeutic target for metastatic EOC. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/11/25/1541-7786.MCR-14-0334/F1.large.jpg
No takes yet. Share an insight, caveat, or question.
Brown et al. (2014) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: