Calcineurin/NFATc1 Pathway Contributes to Cell Proliferation in Hepatocellular Carcinoma

Wang, Shuhuai; Kang, Xinmei; Cao, Shouqiang; Cheng, Hui; Wang, Di; Geng, Jingshu

doi:10.1007/s10620-012-2255-8

Cited by 46 publications

(52 citation statements)

References 16 publications

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“…In contrast to the heart, where calcineurin and NFAT are components of an established pathway that regulates cardiac remodeling (56), little is known about the function of calcineurin/NFAT signaling in the liver (57, 58). Our study suggests that calcineurin/NFAT activation in hepatocytes induces an inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Singh

Grabner

Yanucil

et al. 2016

Kidney International

315

277

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Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature of CKD that predict poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 co-receptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Singh

Grabner

Yanucil

et al. 2016

Kidney International

315

277

View full text Add to dashboard Cite

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“…Calcineurin (CaN) has been reported to be a possible candidate in the signaling of skeletal muscle cellular growth, and plays an important role in regulating cell proliferation34 and differentiation353637. CaN has also been reported to affect the muscle regeneration by association with NFATc1, a downstream target of CaN signaling37.…”

Section: Discussionmentioning

confidence: 99%

Akirin2 regulates proliferation and differentiation of porcine skeletal muscle satellite cells via ERK1/2 and NFATc1 signaling pathways

Chen

Luo

Huang

et al. 2017

Sci Rep

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Akirin2, a novel nuclear factor, plays an important role in myogenesis. To investigate the role of Akirin2 in proliferation and differentiation of porcine skeletal muscle satellite cells, Akirin2 overexpression and Akirin2 silence technologies were employed. Our results showed that overexpression of Akirin2 markedly enhanced the proliferation and differentiation of porcine skeletal muscle satellite cells, whereas silencing of Akirin2 got the opposite results. Furthermore, our results showed that Akirin2 affected proliferation and differentiation of porcine skeletal muscle satellite cells through extracellular-signal regulated kinase-1/2 (ERK1/2) and NFATc1 signaling pathways. These results indicate that Akirin2 can effectively promote skeletal muscle satellite cells proliferation and differentiation, acting through ERK1/2- and NFATc1-dependent mechanisms.

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“…Another study has shown that activation and nuclear translocation of NFAT2 (also known as NFATc1) are increased in proliferating small cholangiocytes [45]. This Ca 2+ /CN/NFATc1 pathway is also associated with cell proliferation in hepatocellular carcinoma [46]. In large cholangiocytes, however, Ca 2+ signaling may not be critical for cell proliferation during cholestatic liver injury.…”

Section: Mechanisms Of Cholangiocyte Proliferation and Functionsmentioning

confidence: 99%

Mechanisms of cholangiocyte responses to injury

Sato

Meng²,

Giang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

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Calcineurin/NFATc1 Pathway Contributes to Cell Proliferation in Hepatocellular Carcinoma

Abstract: The calcineurin/NFATc1 signal is overexpressed and active in HCC. It may enhance the proliferative potential of HepG2 cells through transcriptional activation of the c-myc and cox-2 oncogenes.

Cited by 46 publications

References 16 publications

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Akirin2 regulates proliferation and differentiation of porcine skeletal muscle satellite cells via ERK1/2 and NFATc1 signaling pathways

Mechanisms of cholangiocyte responses to injury

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