Chemokines and hepatocellular carcinoma

Huang, Fan; Geng, Xiaoping

doi:10.3748/wjg.v16.i15.1832

Cited by 61 publications

(50 citation statements)

References 29 publications

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“…Our results show that the tumor-suppressive effects of NCoR are linked to the silencing of genes involved in metastatic spreading, whose expression has been associated with poor prognosis in cancer patients (39)(40)(41)(42)(43)(44). NCoR, together with HDAC3, the main enzyme responsible for the repressive activity of NCoR (45), binds to the promoters of several prometastatic genes, thereby inhibiting histone acetylation and repressing their transcription.…”

Section: Discussionmentioning

confidence: 92%

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Martínez-Iglesias

Alonso-Merino

Gómez-Rey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.nuclear corepressor 1 | thyroid hormone receptor | tumor growth | metastasis | transcription

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Section: Discussionmentioning

confidence: 92%

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Martínez-Iglesias

Alonso-Merino

Gómez-Rey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…MAPK inhibitors modulate chemokine and growth factor secretion in hepatocellular carcinoma but not in healthy liver tissue In liver tissue, cytokines, chemokines, and growth factors are secreted by different cell types and the composition varies between healthy, cirrhotic, and tumor tissue (24)(25)(26). Because chemokine and growth factor secretion by hepatocellular carcinoma cells was modulated by MAPK inhibitors in vitro, we analyzed the effects of sorafenib treatment on the microenvironment on ex vivo liver tissue in a standardized fashion (22,27).…”

Section: Mapk Inhibitors Modulate Chemokine and Growth Factor Secretimentioning

confidence: 99%

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

Breunig

Mueller

Umansky

et al. 2014

Clinical Cancer Research

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Purpose: Small molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, such as sorafenib, represent novel treatment options for advanced hepatocellular carcinoma. The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors.Experimental Design: Hepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis, and chemokine secretion.Results: Hepatocellular carcinoma cell lines responded differentially to these inhibitors in a dosedependent manner, even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis, and chemokine secretion. Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells.Conclusions: Oncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors. Clin Cancer Res; 20(9); 2410-23. Ó2014 AACR.

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“…These molecules regulate inflammation, fibroproliferation, angiogenesis, carcinogenesis, metastasis, and anti-tumour immunity. 59,133,[141][142][143][144] CCL2 is a major HSC-produced chemokine and a critical factor in the induction of liver fibrosis. 145,146 Expression of this chemokine is significantly increased in HSCs and promotes infiltration of the portal tracts with activated macrophages and T lymphocytes.…”

Section: Activatedmentioning

confidence: 99%

The role of chemokines in acute and chronic hepatitis C infection

2013

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Hepatitis C imposes a significant burden on global healthcare. Chronic infection is associated with progressive inflammation of the liver which typically manifests in cirrhosis, organ failure and cancer. By virtue of elaborate evasion strategies, hepatitis C virus (HCV) succeeds as a persistent human virus. It has an extraordinary capacity to subvert the immune response enabling it to establish chronic infections and associated liver disease. Chemokines are low molecular weight chemotactic peptides that mediate the recruitment of inflammatory cells into tissues and back into the lymphatics and peripheral blood. Thus, they are central to the temporal and spatial distribution of effector and regulatory immune cells. The interactions between chemokines and their cognate receptors help shape the immune response and therefore, have a major influence on the outcome of infection. However, chemokines represent a target for modulation by viruses including the HCV. HCV is known to modulate chemokine expression in vitro and may therefore enable its survival by subverting the immune response in vivo through altered leukocyte chemotaxis resulting in impaired viral clearance and the establishment of chronic low-grade inflammation. In this review, the roles of chemokines in acute and chronic HCV infection are described with a particular emphasis placed on chemokine modulation as a means of immune subversion. We provide an in depth discussion of the part played by chemokines in mediating hepatic fibrosis while addressing the potential applications for these chemoattractants in prognostic medicine.

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Chemokines and hepatocellular carcinoma

Cited by 61 publications

References 29 publications

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

The role of chemokines in acute and chronic hepatitis C infection

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