Targeting the inflammation in HCV-associated hepatocellular carcinoma: a role in the prevention and treatment

Both type 2 diabetes (T2D) and chronic hepatitis C (CHC) infection are associated with increased risk of developing hepatocellular carcinoma (HCC). Cytokines are known to play an important role not only in the mechanisms of insulin resistance and glucose disposal defects but also in the pathological processes occurring in the liver during viral infection. We evaluated the serum levels of many cytokines, chemokines, adipokines and growth factors in patients with type 2 diabetes, CHC, CHC-related cirrhosis, CHC and type 2 diabetes and CHC-related cirrhosis and type 2 diabetes by BioPlex assay. The obtained data evidenced that the serum levels of some proteins are significantly up-regulated in all the patients or in those with only one disease and are often higher, even if in different amounts, when both diseases are associated. In particular, our results can be useful for the clinical monitoring of patients because they give specific information in regard to the progression from CHC to LC and CHD to LCD. Moreover, some molecules have shown significant correlations with clinical/biochemical data, suggesting the possibility to define mini-panels that can be used as specific markers for the different disease staging. However, our observations demonstrate that an integrated approach is much more powerful than isolated measurements to evaluate specific stages of these two complex pathologies (type 2 diabetes and chronic CHC hepatitis) alone or when they are concomitant in a patient. In fact it has emerged as an accurate, simple, specific, noninvasive, reproducible and less expensive method that, in future, could be included in routine clinical practice to monitor the association of type 2 diabetes and/or CHC to liver cirrhosis and, possibly, to cancer, and to improve the prognosis of these diseases.

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“…For patients with CHC-related cirrhosis the risk for development of HCC is 0.54 to 2.0% per year [7].…”

Section: Introductionmentioning

confidence: 99%

Cytokinome Profile of Patients with Type 2 Diabetes and/or Chronic Hepatitis C Infection

Costantini¹,

Capone²,

Guerriero³

et al. 2012

PLoS ONE

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“…In addition, serum proinflammatory cytokine levels were higher in hepatitis C virus (HCV)-associated hepatocellular carcinoma patients (12). Modulation of these immune responses represents a potential strategy for ameliorating disease progression (7). Therefore, we aimed to identify new targets for immune modulation as a means of reducing proinflammatory cytokine production by screening a library of natural compounds for the treatment of inflammation-related liver diseases.…”

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confidence: 99%

Mycotoxin Patulin Suppresses Innate Immune Responses by Mitochondrial Dysfunction and p62/Sequestosome-1-dependent Mitophagy

Tsai

et al. 2016

Journal of Biological Chemistry

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Innate immune responses are important for pathogen elimination and adaptive immune response activation. However, excess inflammation may contribute to immunopathology and disease progression (e.g. inflammation-associated hepatocellular carcinoma). Immune modulation resulting from pattern recognition receptor-induced responses is a potential strategy for controlling immunopathology and related diseases. This study demonstrates that the mycotoxin patulin suppresses Toll-like receptor-and RIG-I/MAVS-dependent cytokine production through GSH depletion, mitochondrial dysfunction, the activation of p62-associated mitophagy, and p62-TRAF6 interaction. Blockade of autophagy restored the immunosuppressive activity of patulin, and pharmacological activation of p62-dependent mitophagy directly reduced RIG-I-like receptor-dependent inflammatory cytokine production. These results demonstrated that p62-dependent mitophagy has an immunosuppressive role to innate immune response and might serve as a potential immunomodulatory target for inflammation-associated diseases. Although innate immune responses are critical to pathogen elimination and immune response activation, the pro-inflammatory responses elicited as a result of pattern recognition receptor signaling can lead to excess inflammation if not controlled and may contribute to disease progression (e.g. Helicobacter pylori-associated gastric cancer (3) and chronic hepatitis virus infection-associated hepatocellular carcinoma (4, 5)). Therefore, controlling immunopathology and related diseases caused by inflammation resulting from pattern recognition receptor-dependent signaling represents a potential treatment strategy (6 -8). How to fine tune unwanted inflammation while maintaining protective immune responses intact will be a critical hurdle to overcome.Hepatic diseases, such as cirrhosis and hepatocellular carcinoma are typically associated with chronic inflammation that can take decades to develop. Activation of proinflammatory cytokines in the liver, such as IL-6/gp130/STAT3, is a critical step in the development of hepatic disease, including hepatocellular carcinoma (9 -11). In addition, serum proinflammatory cytokine levels were higher in hepatitis C virus (HCV)-associated hepatocellular carcinoma patients (12). Modulation of these immune responses represents a potential strategy for ameliorating disease progression (7). Therefore, we aimed to identify new targets for immune modulation as a means of reducing proinflammatory cytokine production by screening a library of natural compounds for the treatment of inflammation-related liver diseases. An in vitro screening platform was developed to evaluate natural compounds collected by Microsource Discovery Systems that was composed of two screens: one to evaluate cytokine production activated by LPS/TLR4 pathway signaling and the other to analyze the cytokines triggered by HCV-NS5B-dependent RIG-I/MAVS activation (13). IL-6 production was measured as a readout to evaluate the immune modulatory activity of candidate compou...

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“…HCC incidence is increasing dramatically, with marked variations among geographic areas (El-Serag and Rudolph, 2007) and environmental risk factors (London et al, 1995;Yu and Yuan, 2004). Most HCC cases occur in either sub-Saharan Africa or in Eastern Asia (Castello et al, 2010) and is the most threatening malignancies in Egypt, and counts 4.7% of chronic liver disease patients with rate increasing (Anwar et al, 2008). Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major cause of liver disease worldwide and may contribute directly to the genesis of HCC.…”

Section: Introductionmentioning

confidence: 99%

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

Zekri

Hassan²,

Bahnassy³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Hepatocellular carcinoma (HCC) is a common and aggressive malignancy. Despite of the improvements in its treatment, HCC prognosis remains poor due to its recurrence after resection. This study provides complete genetic profile for Egyptian HCC. Genome-wide analyses were performed to identify the predictive signatures. Patients and Methods: Liver tissue was collected from 31 patients with diagnosis of HCC and gene expression levels in the tumours and their adjacent non-neoplastic tissues samples were studied by analyzing changes by microarray then correlate these with the clinico-pathological parameters. Genes were validated in an independent set by qPCR. The genomic profile was associated with genetic disorders and cancer focused on gene expression, cell cycle and cell death. Molecular profile analysis revealed cell cycle progression and arrest at G2/M, but progression to mitosis; unregulated DNA damage check-points, and apoptosis. Result: Nine hundred fifty eight transcripts out of the 25,000 studied cDNAs were differentially expressed; 503 were up-regulated and 455 were down-regulated. A total of 19 pathways were up-regulated through 27 genes and 13 pathways were down-regulated through 19 genes. Thirty-seven genes showed significant differences in their expression between HCC cases with high and low Alpha Feto Protein (AFP ≥600 IU/ml). The validation for the microarray was done by real time PCR assay in which PPP3CA, ATG-5, BACE genes showed down-regulation and ABCG2, RXRA, ELOVL2, CXR3 genes showed up-regulation. cDNA microarrays showed that among the major upregulated genes in HCC are sets. Conclusion: The identified genes could provide a panel of new diagnostic and prognostic aids for HCC.

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Targeting the inflammation in HCV-associated hepatocellular carcinoma: a role in the prevention and treatment

Cited by 32 publications

References 103 publications

Cytokinome Profile of Patients with Type 2 Diabetes and/or Chronic Hepatitis C Infection

Cytokinome Profile of Patients with Type 2 Diabetes and/or Chronic Hepatitis C Infection

Mycotoxin Patulin Suppresses Innate Immune Responses by Mitochondrial Dysfunction and p62/Sequestosome-1-dependent Mitophagy

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

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