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Tumour necrosis factor-stimulated gene (TSG)-6 controls epithelial–mesenchymal transition of proximal tubular epithelial cells

Bommayya, Girish, Meran, Soma, Krupa, Aleksandra, Phillips, Aled Owain and Steadman, Robert 2011. Tumour necrosis factor-stimulated gene (TSG)-6 controls epithelial–mesenchymal transition of proximal tubular epithelial cells. International Journal of Biochemistry & Cell Biology 43 (12) , pp. 1739-1746. 10.1016/j.biocel.2011.08.009

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Abstract

Progressive renal disease is characterized by accumulation of extracellular matrix in the renal cortex. Proximal tubular cells (PTC) may contribute to disease through a process of epithelial-mesenchymal-transition (EMT): phenotypic change, disruption of the tubular basement membrane and migration into the interstitium. Hyaluronan (HA) synthesis and its extracellular organization by hyaladherins affect cell fate in other systems: this study investigated the role of the hyaladherin, tumour necrosis factor-stimulated gene (TSG)-6, in PTC EMT triggered in vitro by transforming growth factor (TGF)β1. TGFβ1 triggered the loss of PTC epithelial phenotype with 60% decreased expression of E-cadherin and 2-3-fold induction of alpha-smooth muscle actin (α-sma). It also increased the expression of TSG-6, HA-synthase-(HAS)2 and the HA-receptor, CD44, to a peak at 8-12h, remaining elevated thereafter. Immuno-localization of HA demonstrated that unstimulated PTC assembled HA in cables and that treatment with TGFβ1 initiated cable disassembly with formation of dense HA-pericellular coats. Stable knockdown of TSG-6 with short-hairpin-RNA increased E-cadherin and HAS2 expression, produced loose HA-pericellular coats, HA cables were absent and cell migration was slowed. Treatment of transfectants with TGFβ1 did not induce α-sma, alter E-cadherin, pericellular-HA or migration but did induce HAS2. This was dependent on the expression of CD44 and was inhibited by CD44-specific siRNA. In summary, TSG-6 was central to EMT through effects on HA macromolecular structure and through CD44-dependent triggering of cell responses. These findings suggest that controlling the assembly of HA by proximal tubular cells may be a novel approach towards intervention in renal disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Fibrosis; Myofibroblast; Hyaluronan; TSG-6; CD44; Hyaladherin
Publisher: Elsevier
ISSN: 1357-2725
Last Modified: 15 Dec 2017 09:26
URI: http://orca-mwe.cf.ac.uk/id/eprint/23874

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