Abstract
Transforming growth factor β (TGFβ) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGFβ 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 TGFβ signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the α-smooth muscle actin (αSMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high αSMA and low LXRα levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXRα agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGFβ-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXRα antagonized TGFβ signaling at the transcriptional level. Smad3 and LXRα were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGFβ stimulation, and LXRα 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 LXRα agonists limit TGFβ-dependent CAF differentiation, potentially limiting primary HCC growth.
Highlights
Misregulation of transforming growth factor β (TGFβ) signaling occurs in infectious, cardiovascular diseases and cancer[1]
LXRα expression is enriched in epithelial, whereas the TGFβ-induced myofibroblast gene α-smooth muscle actin (αSMA) is enriched in mesenchymal, hepatocellular carcinoma (HCC) We screened HCC cell lines previously classified based on their response to TGFβ signaling, as epithelial-like cells with an early TGFβ target gene signature (Huh[7], PLC/PRF5, Hep3b, HepG2) and as mesenchymal-like cells with a late signature (SNU398, SNU423, HLF, SNU449)[21]
Fig. S1), and T0901317 stimulation induced fatty acid synthase (FASN) in all epithelial HCCs examined, which was easier to detect at the mRNA
Summary
Misregulation of transforming growth factor β (TGFβ) signaling occurs in infectious, cardiovascular diseases and cancer[1]. TGFβ halts cell proliferation and accelerates cell death, as it occurs in immune cells or during liver homeostasis[2,3]. Cellular responses initiate when TGFβ binds to the type II (TβRII) and type I (TβRI) kinase receptor complex[4]. Within this complex, TβRII trans-phosphorylates TβRI, activating TβRI to phosphorylate Smad[2] and Smad[3], which, in complex with Smad[4], regulate gene transcription. The TGFβ receptor activates mitogen activated protein kinase (MAPK), the tyrosine kinase Src and phosphatidylinositol-3 ́-kinase pathways. Upon ligand-induced cleavage, the TβRI intracellular domain regulates transcription[4,5]
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