Raja, R. and Kale , S. and Thorat , D. and Soundararajan , G. and Lohite , K. and Mane , A. and Karnik , S. and Kundu, G.C. (2013) Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1a-mediated VEGF-dependent angiogenesis. Oncogene. pp. 1-12.

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Abstract

Hypoxia is a salient feature of most solid tumors, and hypoxic adaptation of cancer cells has crucial implications in propagation of malignant clonal cell population. Osteopontin (OPN) has been identified as a hypoxia-responsive gene, but the mechanistic and regulatory role of OPN under hypoxia is less characterized. The present study identifies the existence of a positive inter-regulatory loop between hypoxia and OPN. We have shown that hypoxia induces OPN expression in breast cancer cells; however, the expression was found to be HIF1a independent. OPN enabled transcriptional upregulation of HIF1a expression both under normoxia and hypoxia, whereas stability of HIF1a protein in breast cancer cells remained unaffected. Moreover, we have shown that OPN induces integrin-linked kinase (ILK)/Akt-mediated nuclear factor (NF)-kB p65 activation leading to HIF1a-dependent vascular endothelial growth factor (VEGF) expression and angiogenesis in response to hypoxia. These in vitro data are biologically important as OPN expressing cells induce greater tumor growth and angiogenesis through enhanced expressions of proangiogenic molecules as compared with control. Immunohistochemical analysis of human breast cancer specimens revealed significant correlation between OPN and HIF1a but not HIF2a. Elevated expression of HIF1a and OPN was observed in pre-neoplastic and early stage infiltrating ductal carcinoma implicating the role of these proteins in neoplastic progression of breast cancer. Together, our results substantiate the prime role of OPN in cellular adaptation through ILK and NF-kB-mediated HIF1a-dependent VEGF expression in response to hypoxia that ultimately controls breast cancer progression and angiogenesis. Our study reinforces the fact that targeting OPN and its regulated signaling network hold important therapeutic implications.

Item Type:	Article
Subjects:	Cancer Biology
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	13 Apr 2015 09:23
Last Modified:	08 Jul 2015 09:33
URI:	http://nccs.sciencecentral.in/id/eprint/64

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