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Context dependent non canonical WNT signaling mediates activation of fibroblasts by transforming growth factor-beta

Chopra, Sunita and Kumar, Neeraj and Rangarajan, Annapoorni and Kondaiah, Paturu (2015) Context dependent non canonical WNT signaling mediates activation of fibroblasts by transforming growth factor-beta. In: EXPERIMENTAL CELL RESEARCH, 334 (2). pp. 246-259.

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Official URL: http://dx.doi.org/ 10.1016/j.yexcr.2015.03.001


Actions of transforming growth factor-beta are largely context dependent. For instance, TGF-beta is growth inhibitory to epithelial cells and many tumor cell-lines while it stimulates the growth of mesenchymal cells. TGF-beta also activates fibroblast cells to a myofibroblastic phenotype. In order to understand how the responsiveness of fibroblasts to TGF-beta would change in the context of transformation, we have compared the differential gene regulation by TGF-beta in immortal fibroblasts (hFhTERT), transformed fibroblasts (hFhTERT-LTgRAS) and a human fibrosarcoma cell-line (HT1080). The analysis revealed regulation of 6735, 4163, and 3478 probe-sets by TGF-beta in hFhTERT, hFhTERT-LTgRAS and HT1080 cells respectively. Intriguingly, 5291 probe-sets were found to be either regulated in hFhTERT or hFhTERT-LTgRAS cells while 2274 probe-sets were regulated either in hFhTERT or HT1080 cells suggesting that the response of immortal hFhTERT cells to TGF-beta is vastly different compared to the response of both the transformed cells hFhTERT-LTgRAS and HT1080 to TGF-beta. Strikingly, WNT pathway showed enrichment in the hFhTERT cells in Gene Set Enrichment Analysis. Functional studies showed induction of WNT4 by TGF-beta in hFhTERT cells and TGF-beta conferred action of these cells was mediated by WNT4. While TGF-beta activated both canonical and non-canonical WNT pathways in hFhTERT cells, Erk1/2 and p38 Mitogen Activated Protein Kinase pathways were activated in hFhTERT-LTgRAS and HT1080 cells. This suggests that transformation of immortal hFhTERT cells by SV40 large T antigen and activated RAS caused a switch in their response to TGF-beta which matched with the response of HT1080 cells to TGF-beta. These data suggest context dependent activation of non-canonical signaling by TGF-beta. (C) 2015 Published by Elsevier Inc.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the ELSEVIER INC, 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA
Keywords: beta-catenin; Calcium; ERK1/2; P38; Transformation
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited: 19 Jul 2015 06:08
Last Modified: 19 Jul 2015 06:08
URI: http://eprints.iisc.ac.in/id/eprint/51810

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