FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition

Lv, Bei; Ma, Li; Tang, Wenyi; Huang, Peixin; Yang, Biwei; Wang, Lingxiao; Chen, She; Gao, Qiang; Zhang, Si; Xia, Jinglin

doi:10.1159/000491715

Cited by 26 publications

(24 citation statements)

References 52 publications

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“…Among them, FXR activation plays a central role, by inhibiting bile acid synthesis via Cyp7α1, and by exerting several anti-cancer effects, such as suppression of β-catenin expression and function [24, 48]. Very recently, in patients with iCCA, FXR expression has been found to be negatively correlated with the IL-6 level [49]. It is well known that IL-6 has an integral role in iCCA prognosis by acting as a growth and survival factor for CCA cells.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that IL-6 has an integral role in iCCA prognosis by acting as a growth and survival factor for CCA cells. FXR activation inhibited ICC growth and metastasis via IL-6 suppression in vitro and in vivo where counteracting epithelial-mesenchymal transition is a key mechanism [49]. Thus, compelling evidence is emerging on mechanisms which link FXR activation and effects hindering cholangiocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

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The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

et al. 2019

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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 μM) 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 μM. 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

et al. 2019

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“…Furthermore, hepcidin expression has been positively linked with tumor stage 55 and it is activated by IL-6, the latter found up-regulated in CCA tissues. 56 Increased IL-6 levels, typical in a tumoral situation, are also associated with an enhanced Lf, which is known to display a plethora of activities, including the inhibition of carcinogenesis in different tumors, like brain, breast, esophagus, lungs and liver, 21 , 57-61 as well as the anti-inflammatory activity against IL-6 expression in vitro and in vivo . 23 , 38 , 43 , 62-64 We have previously showed that Lf and its receptors are present in biliary epithelium; 65 we found an upregulation in experimental mouse models and in primary biliary cholangitis (PBC), suggesting an increased Lf uptake by damaged cholangiocytes.…”

Section: Discussionmentioning

confidence: 99%

Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma

et al. 2020

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Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy and originates from the neoplastic transformation of the biliary cells. The intrahepatic subtype includes two morpho-molecular forms: large-duct type intrahepatic CCA (iCCA) and small-duct type iCCA. Iron is fundamental for the cellular processes, contributing in tumor development and progression. The aim of this study was to evaluate iron uptake, storage, and efflux proteins in both lipopolysaccharide-inflamed small and large cholangiocytes as well as in different iCCA subtypes. Our results show that, despite an increase in interleukin-6 production by both small and large cholangiocytes, ferroportin (Fpn) was decreased only in small cholangiocytes, whereas transferrin receptor-1 (TfR1) and ferritin (Ftn) did not show any change. Differently from in vitro models, Fpn expression was increased in malignant cholangiocytes of small-duct type iCCA in comparison to large-duct type iCCA and peritumoral tissues. TfR1, Ftn and hepcidin were enhanced, even if at different extent, in both malignant cholangiocytes in comparison to the surrounding samples. Lactoferrin was higher in large-duct type iCCA in respect to small-duct type iCCA and peritumoral tissues. These findings show a different iron handling by inflamed small and large cholangiocytes, and small and large-duct type iCCA. The difference in iron homeostasis by the iCCA subtypes may have implications for the tumor management.

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“…FXR usually express on the surface of liver cells and bile duct cells, and its function is to transport bile acid. Therefore, FXR plays an important role in bile-acid excretion, bile-acid concentration stabilization, and the reabsorption process of bile acid enterohepatic circulation [7][8][9][10]. We previously found that bile salt export pump (Bsep), a target gene of FXR,expression decreased in hilar cholangiocarcinoma tissues of rats.…”

Section: Discussionmentioning

confidence: 99%

FXR expression in a rat model of hilar cholangiocarcinoma

Zhang

Wang

2020

Preprint

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Background: To develop a rat model of hilar cholangiocarcinoma and detect Farnesyl X receptor (FXR) expression in hilar cholangiocarcinoma tissues of this model, in order to provide a new method for the treatment of hilar cholangiocarcinoma.Methods: Forty male Wistar rats (body weight, 185 ± 5 g) were randomly divided into two groups (n = 20 each) as follows: The control group was fed a standard diet, and the experimental group was injected by cholangiocarcinoma QBC939 cell suspension along the hilar bile duct into the bile duct bifurcation with microsyringe. Every day note the rats’ mental state, diet, and fur condition. At 4 weeks, one rat of the experimental group was sacrificed, and we recorded changes in hilar bile duct size, texture, and form. This procedure was repeated at 6 weeks. After 6 weeks, hilar cholangiocarcinoma developed only in the experimental group, thereby establishing an experimental model for studying QBC939-induced hilar cholangiocarcinoma. Tumor formation was confirmed by pathological examination, and hilar bile duct tissues were harvested from both the groups. A real-time polymerase chain reaction assay and an immunohistochemical assay were used to analyze the expression of FXR in hilar cholangiocarcinoma and normal hilar bile duct tissues.Results: From the second week, the rats in experimental group began to eat less, and their body mass decreased compared with controls. After 6 weeks, we detected hilar cholangiocarcinoma in 17 rats (85%) in the experimental group. In the experimental group, we found that the levels of total cholesterol, total bilirubin, and direct bilirubin were higher compared with those of the control group. Simultaneously, muddy stones emerged from the bile ducts of rats in the experimental group. The FXR/Gapdh mRNA ratio in hilar cholangiocarcinoma and normal hilar bile duct tissues differed markedly. Light microscopy revealed a granular pattern of FXR expression which reacted with the anti-FXR antibody. Each section was randomly divided into six regions, with 80 cells were observed in every region. Sections with >10% positive cells were designated positive,Sections with <10% positive cells were designated negative. Each group included 4,800 cells. In the experimental group, 1,196 cells (24.9%) were positive and 3,538 cells (73.7%) were positive in the control group, and this difference was statistically significant.Conclusion: FXR expression significantly decreased in hilar cholangiocarcinoma of rats than in those of controls, suggesting that drugs targeting FXR may be a new strategy for hilar cholangiocarcinoma.

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FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition

Cited by 26 publications

References 52 publications

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma

FXR expression in a rat model of hilar cholangiocarcinoma

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