Role of Osteopontin in Liver Diseases

Wen, Yankai; Jeong, Seogsong; Xia, Qiang; Kong, Xiaoni

doi:10.7150/ijbs.16445

Cited by 84 publications

(83 citation statements)

References 89 publications

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“…To further elucidate the signaling pathways responsible for OPN‐induced CCR1 expression in HCC, we treated HCC cells with several pathways inhibitors, which were reported to be activated by OPN . The results revealed that only blocking the PI3K/AKT pathways by using LY294002 could significantly inhibit the OPN‐induced CCR1 expression, while U0126 or SB203580 did not have similar effects (Figure D).…”

Section: Resultsmentioning

confidence: 99%

C‐C chemokine receptor type 1 mediates osteopontin‐promoted metastasis in hepatocellular carcinoma

et al. 2018

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In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN‐induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C‐C chemokine receptor type 1 (CCR1) and C‐X‐C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN‐promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3‐kinase (PI3K)/AKT and hypoxia‐inducible factor 1α (HIF‐1α) in HCC cells. Furthermore, blockade of OPN‐CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN‐CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.

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Section: Resultsmentioning

confidence: 99%

C‐C chemokine receptor type 1 mediates osteopontin‐promoted metastasis in hepatocellular carcinoma

et al. 2018

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“…Osteopontin, a multifunctional secreted phosphoprotein, induces collagen I expression in HSC by affecting biliary epithelial cells and promoting ductular reaction [86, 87]. Platelets are a source of pro-fibrogenic cytokines and growth factors such as PDGF, TGFβ, and EGF, and they can also suppress collagen expression via HGF-Met signaling pathway [7, 88].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,036

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…Cholangiocytes express and secrete osteopontin (OPN), a multifunctional glycophosphoprotein that can bind to integrin receptors expressed on inflammatory cells and function as a chemoattractant to neutrophils, macrophages and natural killer T cells in the liver (46, 47). Both the expression of osteopontin in biliary epithelial cells and its cleaved form in bile are significantly increased after BDL in mice, presumably caused by the stress on bile epithelial cells that results from the pressure in the biliary systems after obstruction of the bile duct.…”

Section: The Response Of Cholangiocytes To Cholestasismentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

193

120

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Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

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Role of Osteopontin in Liver Diseases

Cited by 84 publications

References 89 publications

C‐C chemokine receptor type 1 mediates osteopontin‐promoted metastasis in hepatocellular carcinoma

C‐C chemokine receptor type 1 mediates osteopontin‐promoted metastasis in hepatocellular carcinoma

Hepatic stellate cells as key target in liver fibrosis

Mechanisms of bile acid mediated inflammation in the liver

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