%0 Journal Article
%T LXR¦Á limits TGF¦Â-dependent hepatocellular carcinoma associated fibroblast differentiation
%J -
%D 2019
%R https://doi.org/10.1038/s41389-019-0140-4
%X Transforming growth factor ¦Â (TGF¦Â) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGF¦Â and undergo myofibroblastic differentiation during tissue wound healing and cancer progression. Cancer-associated fibroblasts (CAFs) communicate with tumor cells during cancer progression, under the guidance of TGF¦Â signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the ¦Á-smooth muscle actin (¦ÁSMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high ¦ÁSMA and low LXR¦Á levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXR¦Á agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGF¦Â-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXR¦Á antagonized TGF¦Â signaling at the transcriptional level. Smad3 and LXR¦Á were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGF¦Â stimulation, and LXR¦Á overexpression repressed the promoter activity. Hepatosphere formation by HCC cells was enhanced upon co-culturing with CAFs. T0901317 suppressed the positive effects exerted on hepatosphere growth by CAFs. Taken together, the data suggest that LXR¦Á agonists limit TGF¦Â-dependent CAF differentiation, potentially limiting primary HCC growth
%U https://www.nature.com/articles/s41389-019-0140-4