Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of β-Catenin

Zheng, Yan; Zhou, Chen; Yu, Xinxin; Wu, Chao; Jia, Hongyan; Gao, Xiaomei; Yang, Jimeng; Wang, Chaoqun; Luo, Qin; Zhu, Ying; Zhang, Yu; Wei, Jie; Sheng, Yuan‐Yuan; Dong, Qiongzhu; Qin, Lun–Xiu

doi:10.1038/s41419-017-0226-x

Cited by 53 publications

(38 citation statements)

References 38 publications

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“…93 Of note, OPN promotes iCCA growth and metastasis by recruiting MEK/MAPK1 and activating Wnt/β-Catenin signaling. 94 Clinical relevance of OPN as putative biomarker was confirmed by molecular profiling of laser-capture microdissected stroma derived from human iCCA, showing marked increase in OPN gene expression levels compared with nontumor tissue, and also, a significant correlation with poor prognosis. 95 Noteworthy, stromal overexpression of OPN and TGF-β2 had the strongest independent predictive power on overall and disease-free survival.…”

Section: Perlecanmentioning

confidence: 94%

Liver Matrix in Benign and Malignant Biliary Tract Disease

et al. 2020

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The extracellular matrix is a highly reactive scaffold formed by a wide array of multifunctional molecules, encompassing collagens and noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and polysaccharides. Besides outlining the tissue borders, the extracellular matrix profoundly regulates the behavior of resident cells by transducing mechanical signals, and by integrating multiple cues derived from the microenvironment. Evidence is mounting that changes in the biostructure of the extracellular matrix are instrumental for biliary repair. Following biliary damage and eventually, malignant transformation, the extracellular matrix undergoes several quantitative and qualitative modifications, which direct interactions among hepatic progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to generate the ductular reaction. Herein, we will give an overview of the main molecular factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we will discuss the structural alterations in terms of biochemical composition and physical stiffness featuring the “desmoplastic matrix” of cholangiocarcinoma along with their pro-oncogenic effects.

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Section: Perlecanmentioning

confidence: 94%

Liver Matrix in Benign and Malignant Biliary Tract Disease

et al. 2020

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“…Prior studies have reported that the phosphorylation of ␤-catenin at Ser 33 -Ser 37 -Thr 41 is essential for ubiquitinationmediated degradation of ␤-catenin (29,30) and the phosphorylation of ␤-catenin at Ser 675 is responsible for ␤-catenin transcriptional activation (31). In our study, we found that the phosphorylated ␤-catenin at Ser 33 -Ser 37 -Thr 41 decreased by 20.1, 42.6, or 65.6%, respectively, in the livers of WT mice treated with 1, 10, or 100 ppm benzene via inhalation.…”

Section: Pp2a Regulates Benzene-induced Hematotoxicity By Suppressionmentioning

confidence: 99%

“…␤-Catenin was sequentially phosphorylated at Ser 33 -Ser 37 -Thr 41 by CKI␣ and GSK3, leading to degradation via the ubiquitination/proteasome machinery (43). In contrast, phosphorylation of ␤-catenin at Ser 675 promoted the nuclear accumulation of ␤-catenin and activation of target gene tran-scription (31). In the current study, we found that the dephosphorylation of ␤-catenin at Ser 33 /Ser 37 /Thr 41 in benzenetreated mouse liver led to up-regulation of ␤-catenin and, in turn, activation of cyp2e1 transcription.…”

Section: Pp2a Regulates Benzene-induced Hematotoxicitymentioning

confidence: 99%

Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of cytochrome P4502E1

Chen

Guo

Zhang

et al. 2019

Journal of Biological Chemistry

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Edited by Joel M. GottesfeldChronic benzene exposure is associated with hematotoxicity and the development of aplastic anemia and leukemia. However, the signaling pathways underlying benzene-induced hematotoxicity remain to be defined. Here, we investigated the role of protein phosphatase 2A (PP2A) in the regulation of benzeneinduced hematotoxicity in a murine model. Male mice with a hepatocyte-specific homozygous deletion of the Ppp2r1a gene (encoding PP2A A␣ subunit) (HO) and matched wildtype (WT) mice were exposed to benzene via inhalation at doses of 1, 10, and 100 ppm for 28 days. Peripheral white blood cell counts and activation of bone marrow progenitors were attenuated in the HO mice, indicating that Ppp2r1a deletion protects against benzene-induced hematotoxicity. Moreover, elevation of urinary S-phenyl mercapturic acid, a benzene metabolite, was much greater in WT mice than in HO mice. Real-time exhalation analysis revealed more exhaled benzene but fewer benzene metabolites in HO mice than in WT mice, possibly because of the down-regulation of Cyp2e1, encoding cytochrome P4502E1, in hepatocytes of the HO mice. Loss-of-function screening disclosed that PP2A complexes containing the B56␣ subunit participate in regulating Cyp2e1 expression. Notably, PP2A-B56␣ suppressioninHepG2cellsresultedinpersistent␤-cateninphosphorylation at Ser 33 -Ser 37 -Thr 41 in response to CYP2E1 agonists. In parallel, nuclear translocation of ␤-catenin was inhibited, concomitant with a remarkable decrease of Cyp2e1 expression. These findings support the notion that a regulatory cascade comprising PP2A-B56␣, ␤-catenin, and Cyp2e1 is involved in benzene-induced hematotoxicity, providing critical insight into the role of PP2A in responses to the environmental chemicals.

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“…OPN is involved in NAFLD pathogenesis (Kiefer et al., 2011), and its liver expression is increased in obesity and correlates with steatosis and insulin resistance (Gómez‐Ambrosi et al., 2007). OPN expression is also upregulated in liver cancers such as in HCC and cholangiocarcinoma (Wen, Jeong, Xia, & Kong, 2016; Zheng et al., 2018). Regarding its role as a metabolic modulator, it controls the fate of acetyl‐CoA in liver (Nunez‐Garcia et al., 2017; Nuñez‐Garcia et al., 2018) and rewires liver lipid metabolism after partial hepatectomy (Nuñez‐Garcia et al., 2018).…”

Section: Introductionmentioning

confidence: 99%