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LXR? limits TGF?-dependent hepatocellular carcinoma associated fibroblast differentiation.

ABSTRACT: Transforming growth factor ? (TGF?) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGF? 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? signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the ?-smooth muscle actin (?SMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high ?SMA and low LXR? levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXR? agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGF?-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXR? antagonized TGF? signaling at the transcriptional level. Smad3 and LXR? were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGF? stimulation, and LXR? 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? agonists limit TGF?-dependent CAF differentiation, potentially limiting primary HCC growth.

SUBMITTER: Moren A

PROVIDER: S-EPMC6522550 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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LXRα limits TGFβ-dependent hepatocellular carcinoma associated fibroblast differentiation.

Morén Anita A Bellomo Claudia C Tsubakihara Yutaro Y Kardassis Dimitris D Mikulits Wolfgang W Heldin Carl-Henrik CH Moustakas Aristidis A

Oncogenesis 20190516 6

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 ...[more]

PMID: 31097694

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Project description:Hepatocellular carcinoma (HCC) is a global health challenge with an increasing incidence worldwide. Cancer-associated fibroblasts (CAFs) function critically in HCC initiation and development. However, the prognostic significance of CAF-related gene signatures in HCC remains unknown. Therefore, the specific functions of CAF-related genes in HCC were investigated to help develop potential therapeutic strategies. In this study, CAF-related genes were screened from three CAF-related gene sets. HCC data from the Gene Expression Omnibus (GEO) database was applied to verify the screened CAF-related genes. Cluster analysis was used to identify clusters based on the expression pattern of CAF-related genes and two identified clusters were found to have a significant difference in overall survival (OS) and progression free intervals (PFI). The prognosis of HCC patients was predicted using the prognostic risk score model developed based on HCC data from The Cancer Genome Atlas (TCGA) databases. High-risk group patients had a worse OS than those in low-risk group in TCGA. These results were validated in International Cancer Genome Consortium (ICGC) database. Moreover, combining the clinicopathological characteristics related to prognosis with the model, a nomogram was built for a more accurate prediction of OS of HCC patients. In addition, analyses of immune infiltration characteristics of tumor microenvironment (TME), chemosensitivity, and immunotherapy response were conducted to further evaluate the prognostic value of CAF-related genes. Patients with low-risk scores were found to have higher chemosensitivity to cisplatin, doxorubicin, and sorafenib. Individuals with high-risk scores were found with a higher expression of most immune checkpoints which indicated patients with high-risk scores may benefit more from treatment with immune checkpoint inhibitors. Furthermore, a correlation between immune infiltration characteristics of TME and patients with different risk levels was found. These findings provide a possibility for the further development of personalized treatments in HCC.

Dataset Information

LXR? limits TGF?-dependent hepatocellular carcinoma associated fibroblast differentiation.

Publications

LXRα limits TGFβ-dependent hepatocellular carcinoma associated fibroblast differentiation.

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