Dataset Information

The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway.

ABSTRACT: The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored. Cytotoxicity studies were performed on HepG2, Huh7, and SNU-449 cell lines using OCA alone and combined with the FXR antagonist guggulsterone (Gugg). OCA cytotoxic effect was significantly hampered in presence of Gugg. OCA also caused cell cycle arrest and inhibited invasion and migration of HCC cells. Decrease in STAT3 phosphorylation and SOCS3 upregulation were also observed. Moreover, Jak-2, IL-1?, and IL-6 levels were decreased. These results were correlated with an upregulation of FXR and small heterodimer partner (SHP) levels. Effects of OCA on IL-6/STAT3 main key players were reversed in presence of Gugg. Overall, these findings suggest a potential effect of OCA in HCC via interfering with IL-6/STAT3 signalling pathway in vitro.

SUBMITTER: Attia YM

PROVIDER: S-EPMC5624958 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway.

Attia Yasmeen M YM Tawfiq Rasha A RA Ali Aya A AA Elmazar Mohamed M MM

Scientific reports 20171002 1

The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppres ...[more]

PMID: 28970500

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Project description:Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0-2.5 ?M) of OCA were added to culture media and, after 3-10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 ?M. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.

Dataset Information

The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway.

Publications

The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway.

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