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

被引：5
作者：
Chopra, Sunita [1 ]
Kumar, Neeraj [1 ]
Rangarajan, Annapoorni [1 ]
Kondaiah, Paturu [1 ]
机构：
[1] Indian Inst Sci, Dept Mol Reprod Dev & Genet, Bangalore 560012, Karnataka, India
来源：
EXPERIMENTAL CELL RESEARCH | 2015年 / 334卷 / 02期
关键词：
beta-catenin; Calcium; ERK1/2; P38; Transformation; HUMAN LUNG FIBROBLASTS; TGF-BETA; PHOSPHATIDYLINOSITOL; 3-KINASE; PHENOTYPIC MODULATION; TUMOR-SUPPRESSOR; CANCER; EXPRESSION; RECEPTOR; PATHWAYS; SMAD3;
D O I：
10.1016/j.yexcr.2015.03.001
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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.
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收藏
页码：246 / 259
页数：14
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