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Transcriptional profiling identifies functional interactions of TGF ? and PPAR ?/? signaling: synergistic induction of ANGPTL4 transcription.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) not only play a key role in regulating metabolic pathways but also modulate inflammatory processes, pointing to a functional interaction between PPAR and cytokine signaling pathways. In this study, we show by genome-wide transcriptional profiling that PPAR?/? and transforming growth factor-? (TGF?) pathways functionally interact in human myofibroblasts and that a subset of these genes is cooperatively activated by TGF? and PPAR?/?. Using the angiopoietin-like 4 (ANGPTL4) gene as a model, we demonstrate that two enhancer regions cooperate to mediate the observed synergistic response. A TGF?-responsive enhancer located ?8 kb upstream of the transcriptional start site is regulated by a mechanism involving SMAD3, ETS1, RUNX, and AP-1 transcription factors that interact with multiple contiguous binding sites. A second enhancer (PPAR-E) consisting of three juxtaposed PPAR response elements is located in the third intron ?3.5 kb downstream of the transcriptional start site. The PPAR-E is strongly activated by all three PPAR subtypes, with a novel type of PPAR response element motif playing a central role. Although the PPAR-E is not regulated by TGF?, it interacts with SMAD3, ETS1, RUNX2, and AP-1 in vivo, providing a possible mechanistic explanation for the observed synergism.

SUBMITTER: Kaddatz K

PROVIDER: S-EPMC2937979 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Transcriptional profiling identifies functional interactions of TGF β and PPAR β/δ signaling: synergistic induction of ANGPTL4 transcription.

Kaddatz Kerstin K Adhikary Till T Finkernagel Florian F Meissner Wolfgang W Müller-Brüsselbach Sabine S Müller Rolf R

The Journal of biological chemistry 20100701 38

Peroxisome proliferator-activated receptors (PPARs) not only play a key role in regulating metabolic pathways but also modulate inflammatory processes, pointing to a functional interaction between PPAR and cytokine signaling pathways. In this study, we show by genome-wide transcriptional profiling that PPARβ/δ and transforming growth factor-β (TGFβ) pathways functionally interact in human myofibroblasts and that a subset of these genes is cooperatively activated by TGFβ and PPARβ/δ. Using the an ...[more]

PMID: 20595396

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Project description:Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and the fourth leading cause of cancer mortality worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. A number of distinct molecules have been recently identified as playing a role in the control of cancer progression. However, patients with HCC have a highly variable clinical course, indicating that HCC comprises several biologically distinctive subgroups reflecting a molecular heterogeneity of the tumors. To evaluate potential biomarkers in HCC, we employed multiple methods in this study, including qPCR, immunostaining methods and tissue microarrays (TMAs), as well as histological and pathological analysis, to assess TGF?, XPO4, elF5A2 and ANGPTL4 in cancerous and paracancerous liver tissues from 280 patients suffering from liver cancer. Our results found that all four indicators were located in the cytoplasm and distributed in cancerous and paracancerous liver tissues. Generally, there were higher levels of these indicators in paracancerous, compared with cancerous, liver tissues. These four indicators were correlated and modulated among each other. In connection with patient clinical and revisit information, statistical analysis determined that TGF?1 in paracancerous liver tissue was positively correlated with tumor size. Higher production of TGF?1 in paracancerous liver tissue was always associated with bigger liver tumors. XPO4 in cancerous liver tissue and TGF?1 in paracancerous liver tissue were positively correlated with tumor differentiation. TGF?1, ANGPTL4 and elF5A2 were also positively correlated with the T classification of tumors. Additionally, higher levels of XPO4 in cancerous liver tissue suggested that the patient would have a better prognosis and survival rate. However, higher production of XPO4 in paracancerous liver tissue suggested a worse prognosis. All the results above provide new insights into better understanding biological indicators, such as XPO4, TGF?1, ANGPTL4 and elF5A2, in the prediction and evaluation of liver cancer, as well as signaling pathways in the control of liver cancer. XPO4 and TGF?1 may serve as useful markers to evaluate the size and prognosis of liver cancer.

Dataset Information

Transcriptional profiling identifies functional interactions of TGF ? and PPAR ?/? signaling: synergistic induction of ANGPTL4 transcription.

Publications

Transcriptional profiling identifies functional interactions of TGF β and PPAR β/δ signaling: synergistic induction of ANGPTL4 transcription.

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