JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

Smirnova, O. Yu.

doi:10.3748/wjg.13.6478

Cited by 19 publications

(21 citation statements)

References 143 publications

(189 reference statements)

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“…Sustained cell proliferation in a micro-environment rich in inflammatory cells, cytokines/chemokines, growth factors and DNA-damaging agents (such as reactive oxygen and nitrogen species because of long-term inflammation) will lead to permanent genetic alterations and subsequent neoplastic transformation of the proliferating cells (Komori et al, 2008). For example, interleukin-6, an inflammatory cytokine, promotes human cholangiocarcinoma cells grown in vivo by inhibiting apoptosis through the activation of miRNAs including miR let-7a and miR370, thereby modulating the activation of STAT-3 pathways (Meng et al, 2007(Meng et al, , 2008Smirnova et al, 2007). It has also been shown that the sustained upregulation of the transcription factor nuclear factor kappaB (NF-kB) in the liver cells, through the paracrine action of tumour necrosis factor-a secreted from the neighbouring endothelia and inflammatory cells, may lead to the tumour development (Maeda et al, 2005;Choi et al, 2006;Sakurai et al, 2006;Luedde et al, 2007), given the activation of mitogenic and anti-apoptotic genes through NF-kB pathways.…”

Section: Discussionmentioning

confidence: 99%

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

et al. 2009

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Bile duct cells and hepatocytes differentiate from the same hepatic progenitor cells. To investigate the possible association of viral hepatitis B and C with intrahepatic cholangiocarcinoma (ICC), we conducted a retrospective case -control study using univariate and multivariate logistic analyses to identify risk factors for ICC. Besides hepatic lithiasis (25.6%; Po0.001), seropositivity for hepatitis B surface antigen (37.5% of all ICC patients; odds ratio (OR) ¼ 4.985, Po0.001) and seropositivity for hepatitis C antibodies (13.1%; OR ¼ 2.709; P ¼ 0.021) are the primary independent risk factors for ICC. Cirrhosis exerted synergic effects on the development of ICC. We compared the age distributions of viral-hepatitis associated ICC to that of viral hepatitis-associated hepatocellular carcinoma (HCC). The mean age of ICC patients with viral hepatitis B (56.4 ± 11.1 years) were 9 years younger than that of ICC patients with viral hepatitis C (65.6 ± 9.17 years), similar to that observed in HCC. The incidence ratio of HCC : ICC : CHC (combined hepatocellular cholangiocarcinoma) in our population was 233 : 17 : 1 consistent with the theoretic ratio of hepatocyte number to cholangiocyte number in the liver. Our findings indicated that both viral hepatitis-associated ICC and HCC shared common disease process for carcinogenesis and, possibly, both arose from the hepatic progenitor cells.

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Section: Discussionmentioning

confidence: 99%

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

et al. 2009

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“…The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway participates in the regulation of cell proliferation, differentiation, survival, motility and apoptosis in many organs, including liver [23,24] . STAT3 plays a critical role in transcriptional regulation of genes and is also activated by many cytokines and growth factor receptors, such as PDGFR, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) through JAK [25,26] .…”

Section: Jak-stat Pathway and Sorafenib Resistancementioning

confidence: 99%

“…STAT3 plays a critical role in transcriptional regulation of genes and is also activated by many cytokines and growth factor receptors, such as PDGFR, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) through JAK [25,26] . The negative regulation of STAT3 is mainly executed by suppression of cytokine signaling (SOCS) proteins through JAK and Src-homology protein tyrosine phosphatases (SHPs), such as SHP-1 and SHP-2, and cytokines and growth factor receptors [23] . STAT3 is activated in HCC and knockdown of STAT3 had a therapeutic effect on HCC [27] .…”

Section: Jak-stat Pathway and Sorafenib Resistancementioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

156

148

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Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352 Available from:

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“…Binding of specific ligands to cytokines receptors leads to receptor dimerization and cross-activation of receptor-associated JAK kinases, which in turn phosphorylates tyrosine, leading to changes of intercellular parts of receptors and subsequent activation of receptor-associated JAKs, followed by STAT docking and phosphorylation (6,7). Phosphorylated STAT dimers can bind to STAT-responsive elements in the promoters of various genes, resulting in modulation of their transcriptions (8). Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine receptor signaling by several distinct mechanisms (7).…”

Section: Introductionmentioning

confidence: 99%

“…SOCSs directly inhibit JAK kinases by binding to the receptor or to the JAK activation loop (7). SOCS proteins compete with STATs for binding sites on the receptor by SH2 domains (8). In addition, SOCS proteins can target the receptor complex and associated signaling proteins for proteasomal degradation through their SOCS boxes, which mediate interactions with elongins B and C to recruit an E3 ubiquitin ligase complex (9,10).…”

Section: Introductionmentioning

confidence: 99%

Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells

Kuo

Tsai

et al. 2009

Molecular Cancer Therapeutics

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This study investigates the anticancer effect of dehydrocostuslactone (DHE), a plant-derived sesquiterpene lactone, on human breast cancer cells. DHE inhibits cell proliferation by inducing cells to undergo cell cycle arrest and apoptosis. DHE suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G 0 /G 1 -S phase arrest in MCF-7 cells. In contrast, DHE caused S-G 2 /M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. DHE induces up-regulation of Bax and Bad, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor and endonuclease G. We also found that DHE inhibits survival signaling through the Janus tyrosine kinase-signal transducer and activator of transcription-3 signaling by increasing the expression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell cycle progression and cell death through SOCS-1 and SOCS-3. Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer.

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JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

Cited by 19 publications

References 143 publications

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells

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