• Chemokines
• Chronic hepatitis C infection
• Fibrosis
• Polymorphism

• Humans
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/blood
• Hepatitis C, Chronic/pathology
• Hepatitis C, Chronic/virology
• Female
• Male
• Biomarkers/blood
• Liver Cirrhosis/genetics
• Liver Cirrhosis/blood
• Liver Cirrhosis/virology
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• Adult
• Chemokine CXCL12/genetics
• Chemokine CXCL12/blood
• Chemokine CXCL16/genetics
• Chemokine CXCL16/blood
• Chemokine CXCL11/blood
• Chemokine CXCL11/genetics
• Genotype
• Case-Control Studies
• Chemokines/blood
• Chemokines/genetics

• [2021-1-TP2-4131] Mersin University Scientific Research Projects (BAP)
• [2021-1-TP2-4131] Mersin University Scientific Research Projects (BAP)

• Biomarkers
• Colorectal liver metastases
• Computed tomography
• Machine learning analysis
• Magnetic resonance imaging
• Radiomics analysis

• Humans
• Prognosis
• Retrospective Studies
• Tomography, X-Ray Computed/methods
• Magnetic Resonance Imaging/methods
• Liver Neoplasms/diagnostic imaging
• Colorectal Neoplasms/diagnostic imaging
• Machine Learning

• LI-RADS
• diagnosis
• liver

Chronic liver disease is a major health issue worldwide and chronic hepatitis C (CHC) is associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC). There is evidence that the hepatitis C virus (HCV) infection is correlated with immune senescence by way of immune activation and chronic inflammation, which lead to increased metabolic and cardiovascular risk, as well as progressive liver damage. Both the innate and adaptive immunity are firmly tied to the prognosis of an infection with HCV and its response to antiviral therapy. HCV is therefore associated with increased pro-inflammatory status, heightened production of cytokines, prolonged systemic inflammation, as well as increased morbidity and mortality, mainly due to the progression of hepatic fibrosis and HCC, but also secondary to cardiovascular diseases. Viral hepatic pathology is increasingly considered a disease that is no longer merely limited to the liver, but one with multiple metabolic consequences. Numerous in vitro studies, using experimental models of acute or chronic inflammation of the liver, has brought new information on immunopathological mechanisms resulting from viral infections and have highlighted the importance of involving complex structures, inflammasomes complex, in these mechanisms, in addition to the involvement of numerous proinflammatory cytokines. Beyond obtaining a sustained viral response and halting the aforementioned hepatic fibrosis, the current therapeutic “treat-to-target” strategies are presently focused on immune-mediated and metabolic disorders, to improve the quality of life and long-term prognosis of CHC patients.

• CD136
• HCV
• IL-17
• IL-4
• IL-6

• Antigens, CD/metabolism
• Antigens, Differentiation, Myelomonocytic/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Genetic Predisposition to Disease
• Genotype
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/metabolism
• Humans
• Interleukin-17/metabolism
• Interleukin-4/metabolism
• Interleukin-6/genetics
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Receptors, Cell Surface/metabolism

The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon‐free direct‐acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance.

Here, we aimed at evaluating the effects of direct‐acting antiviral therapy‐induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct‐acting antiviral‐mediated hepatitis C clearance in cirrhosis patients was investigated.

Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct‐acting antiviral treatment.

Elevated pretherapy concentrations of specific soluble immune mediators including MCP‐3, GDNF, CDCP1, IL‐17C, IL‐17A, signalling lymphocytic activation family 1, CCL11, FGF‐5, LIF‐R, interleukin 10 (IL‐10), IL‐10RA, IL‐15RA, beta NGF, CCL28, CCL25 and NT‐3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF‐5 and IL‐15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma‐free patients experienced significant ameliorations.

These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct‐acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct‐acting antiviral therapies would be superior to the risk of developing carcinoma.

Established knowledge on this subject

Current interferon (IFN)‐free direct‐acting antivirals (DAAs) are effective at eliminating hepatitis C virus (HCV), but risks of residual liver disease and development of hepatocellular carcinoma persists.

Significant and/or new findings of this study

An elevated pre‐therapy plasma profile of an extended repertoire of SIMs in cirrhosis was associated with HCC development post‐DAA therapy.

• chemokines
• cytokines
• direct-acting antivirals
• hepatitis C
• hepatitis C virus cirrhosis
• hepatocellular carcinoma
• interferon-free therapy
• soluble immune mediators

Gamma-glutamyltransferase (GGT) is involved in tumor development and progression, but its prognostic value in α-fetoprotein- (AFP-) negative (AFP < 25 ng/mL) hepatocellular carcinoma (HCC) patients remains unknown.

A large cohort of 678 patients with AFP-negative HCC following curative resection who had complete data were enrolled in this study. The optimal cutoff value for the preoperative level of GGT was determined by the X-tile program. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were also identified.

The optimal cutoff values for the preoperative levels of GGT were 37.2 U/L and 102.8 U/L, which were used to divide all patients into three subgroups (group 1, GGT < 37.2 U/L (n = 211, 31.1%); group 2, GGT ≥ 37.2 and <102.8 U/L (n = 320, 47.2%); group 3, GGT ≥ 102.8 U/L (n = 147, 21.7%)), with distinct OS times (58.5 vs. 53.5 vs. 44.4 months, P < 0.001) and DFS times (47.9 vs. 40.3 vs. 30.1 months, P < 0.001). Elevated preoperative GGT levels were associated with an unfavorable tumor burden (larger tumor size, multiple tumors, and microvascular invasion) and were selected as independent predictors of a worse OS (group 2 vs. group 1, HR: 1.73 (1.13-2.65), P = 0.011; group 3 vs. group 1, HR: 3.28 (2.10-5.13), P < 0.001) and DFS (group 2 vs. group 1, HR: 1.52 (1.13-2.05), P = 0.006; group 3 vs. group 1, HR: 2.11 (1.49-2.98), P < 0.001) in multivariable analysis.

Elevated preoperative GGT levels are associated with an unfavorable tumor burden and serve as an independent prognostic marker for worse outcomes in AFP-negative HCC patients following resection.

Hepatitis C virus (HCV) infects 180 million people worldwide and over 4 million people in the United States. HCV infection is a major cause of chronic liver disease and is recognized as a risk factor for clinical cardiovascular disease (CVD). Many studies have shown increased prevalence of cardiac and inflammatory biomarkers in patients with chronic HCV infection (CHC), and though these markers may be used to risk stratify people for cardiac disease in the general population their role in the HCV population is unknown. Patients with CHC have elevated cardiac and inflammatory biomarkers compared to noninfected controls which may play a role in CVD risk stratification. We undertook a systematic review of inflammatory and cardiac biomarkers in people with HCV infection with a focus on the effect of CHC on serum levels of these markers and their utility as predictors of CVD in this population. Medline, EMBASE, and Cochrane databases were searched for relevant articles until June 2019. A total of 2430 results were reviewed with 115 studies included. Our review revealed that HCV infection significantly alters serum levels of markers of inflammation, endothelial function, and cardiac dysfunction prior to HCV treatment, and some of which may change in response to HCV therapy. Current risk stratification tools for development of CVD in the general population may not account for the increased inflammatory markers that appear to be elevated among HCV‐infected patients contributing to increased CVD risk.

• biomarkers
• cardiac biomarkers
• chronic hepatitis C infection
• hepatitis C
• inflammatory biomarkers

• Hepatocellular carcinoma
• Homing
• In vivo flow cytometry
• Mesenchymal stem cells
• Tumor xenograft model

• Animals
• Carcinoma, Hepatocellular/therapy
• Cell Line, Tumor
• Disease Models, Animal
• Flow Cytometry
• Humans
• Kinetics
• Liver Neoplasms/therapy
• Male
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/physiology
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays

To analyze cytokine levels and to identify their association with outcome in patients with hepatocellular carcinoma (HCC) treated with radiotherapy (RT).

Patients with HCC who were treated with RT were eligible for this prospective study. Blood samples were collected before and after RT, and serum cytokine levels including interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor-α were analyzed.

Between 2008 and 2009, 51 patients were enrolled in this study. Baseline IL-6 level was high in patients with a history of pre-RT treatment. Median survival was 13.9 mo with alpha-fetoprotein (AFP) as a significant factor (P = 0.020). Median failure-free survival (FFS) for infield, outfield-intrahepatic and extrahepatic failures were 23.3, 11.5 and 12.0 mo, respectively. Sex and baseline IL-6 level were associated with infield FFS, and baseline IL-10 level was correlated with outfield-intrahepatic FFS. For extrahepatic FFS, AFP was significant (P = 0.034). Patients with a baseline IL-6 level of ≥ 9.7 pg/mL showed worse infield FFS (P = 0.005), and this significance was observed only in treatment-non-naïve patients (P = 0.022).

In addition to AFP, cytokines seem useful in predicting infield and outfield-intrahepatic failure. Serum cytokines could be useful biomarkers for predicting RT outcome in HCC.

• Hepatocellular carcinoma
• Radiotherapy
• Cytokine
• Interleukin-6

• Adult
• Aged
• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/radiotherapy
• Cytokines/blood
• Female
• Humans
• Interleukins/blood
• Liver Neoplasms/blood
• Liver Neoplasms/mortality
• Liver Neoplasms/radiotherapy
• Male
• Middle Aged
• Prognosis
• Prospective Studies
• Survival Rate
• Treatment Outcome
• Tumor Necrosis Factor-alpha/blood

In this study, a hydroalcoholic chestnut shell extract was characterized and tested on six different human cell lines. Gallic, ellagic, and syringic acids were the most abundant non-condensed compounds in the chestnut extract, as determined by high performance liquid chromatography (HPLC). Tannins were mainly represented by condensed monomeric units of epigallocatechin and catechin/epicatechin. After 48 h of treatment, only the human hepatoblastoma HepG2 cells reached an inhibition corresponding to IC₅₀ with an increase of apoptosis and mitochondrial depolarization. The cytokinome evaluation before and after treatment revealed that the vascular endothelial growth factor (VEGF) and the tumor necrosis factor (TNF)-α decreased after the treatment, suggesting a potential anti-angiogenic and anti-inflammatory effect of this extract. Moreover, the metabolome evaluation by ¹H-NMR evidenced that the polyphenols extracted from chestnut shell (PECS) treatment affected the levels of some amino acids and other metabolites. Overall, these data highlight the effects of biomolecules on cell proliferation, apoptosis, cell cycle and mitochondrial depolarization, and on cytokinomics and metabolomics profiles.

• cancer
• chestnut shells extract
• polyphenols

• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Chromatography, High Pressure Liquid
• Cytokines/metabolism
• Ellagic Acid/chemistry
• Ellagic Acid/pharmacology
• Fagaceae/chemistry
• Gallic Acid/analogs & derivatives
• Gallic Acid/chemistry
• Gallic Acid/pharmacology
• Gene Expression Regulation, Neoplastic/drug effects
• HT29 Cells
• Hep G2 Cells
• Humans
• MCF-7 Cells
• Metabolome/drug effects
• Mitochondria/drug effects
• Plant Exudates/chemistry
• Plant Exudates/pharmacology
• Polyphenols/chemistry
• Polyphenols/pharmacology
• Tannins/chemistry
• Tannins/pharmacology

Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC.

• Hepatocellular carcinoma
• Hepatitis C virus
• Hepatitis B virus
• Cytokines
• Polymorphism

• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/immunology
• Cytokines/genetics
• Hepatitis B/complications
• Hepatitis C/complications
• Humans
• Liver Neoplasms/etiology
• Liver Neoplasms/genetics
• Liver Neoplasms/immunology
• Polymorphism, Single Nucleotide
• Th1 Cells/immunology

• RIG-I-like receptor (RLR)
• immunomodulation
• mitochondria
• mitophagy
• mycotoxin
• p62 (sequestosome 1(SQSTM1))
• patulin
• toll-like receptor (TLR)

Vitamin D levels play a pivotal role in most biological processes and differ according to age. A deficiency of vitamin D in chronic hepatitis C (CHC) patients has been shown to be linked with the severity of liver fibrosis, but little is known about the mechanism of this association.

In this study, we evaluate the potential interrelation between vitamin D levels, oxidative stress, and apoptosis, based on liver fibrosis in geriatric patients infected with hepatitis C virus (HCV) genotype 4.

A total of 120 adult individuals aged 30–68 years were recruited in this study. Of these, 20 healthy subjects (15 men and five women) with a mean age of 48.3±6.1 years were selected as controls, and 100 patients with a mean age of 47.8±4.9 years with chronic HCV (CHC) who had undergone liver biopsy (80 men and 20 women) were included in this study. Based on liver radiographic (computed tomography, magnetic resonance imaging) and histological Metavir system analyses, the CHC patients were classified into three groups: asymptomatic CHC carriers (n=30), fibrosis (n=25), and cirrhosis (n=45). HCV RNA, HCV genotypes, inflammatory cytokines AFP and TNFα, 25-hydroxyvitamin D (25[OH]D) levels, apoptotic markers single-stranded DNA (ssDNA) and soluble Fas (sFas), and oxidative stress markers nitric oxide (NO) and total antioxidant capacity (TAC) were estimated by using molecular, immunoassay, and colorimetric techniques.

Approximately 30% of the study population (n=30) were diagnosed as asymptomatic CHC carriers, and 70% of the study population (n=70) had severe fibrosis; these were classified into fibrosis and cirrhosis. There was a significant reduction in 25(OH)D levels and TAC activity, along with an increase in levels of NO, AFP, TNFα, ssDNA, and sFas in fibrosis and cirrhosis subjects compared with those of asymptomatic CHC carriers and health controls. The deficiency in 25(OH)D levels correlated positively with sFas, ssDNA, AFP, TNFα, NO, and TAC, and negatively with age, sex, liver function, body mass index, homeostatic model assessment – insulin resistance, HCV RNA, and viral load. Significant intercorrelation was reported between serum 25(OH)D concentrations and apoptotic and oxidative markers, which suggested progression of liver pathogenesis and fibrogenesis via oxidative and apoptotic mechanisms.

The data showed that vitamin D status was significantly correlated with pathogenesis and fibrogenesis of the liver in geriatric patients infected with HCV genotype 4. The deficiency in 25(OH)D levels was shown to have a pivotal role in the pathogenesis of liver via apoptotic, oxidative stress, and inflammatory mechanistic pathways. The data point to adequate vitamin D levels being recommended for a good response to treatment strategies, especially in older CHC patients.

• 25(OH)D
• Fas antigen
• HCV
• apoptosis
• geriatrics
• liver fibrosis
• oxidative stress

The current study was designed to investigate the potential association of serum interleukin-10 and interleukin-12 with HCV infection in chronic liver disease and to evaluate their possible role as new biomarkers in HCC development. Material and Methods. Forty-one patients suffering from chronic liver disease (33 patients harbor HCV infection and 8 are HCV-negative patients) were enrolled in the present study and histopathologically diagnosed into 15 patients with HCC, 16 patients with LC, and 10 patients with liver histology compatible with precirrhotic hepatitis (PCH). Ten patients complaining of cholecystitis were included as nondisease control. Serum levels of IL-10 and IL-12 were measured by enzyme linked immunosorbent assay (ELISA). Results. HCV-infected patients showed elevated expression of IL-10 and IL-12 compared to nondisease controls (P < 0.0001) but there is no significant difference with respect to their expression in HCV-negative patients. Serum IL-10 and IL-12 were elevated significantly with disease progression (P < 0.0001) and a positive correlation coefficient was detected between IL-10, IL-12 (r = 0.785, P < 0.0001), and transaminase values suggesting their possible role in chronic inflammation progression leading to HCC. Conclusion. IL-10 and IL-12 might be involved in chronic inflammation progression leading to HCC and their evaluation could be used as new biomarkers to reflect the degree of inflammation in HCC development.

Understanding the dynamics of the complex interaction network of cytokines, defined as ‘‘cytokinome’’, can be useful to follow progression and evolution of hepatocellular carcinoma (HCC) from its early stages as well as to define therapeutic strategies. Recently we have evaluated the cytokinome profile in patients with type 2 diabetes (T2D) and/or chronic hepatitis C (CHC) infection and/or cirrhosis suggesting specific markers for the different stages of the diseases. Since T2D has been identified as one of the contributory cause of HCC, in this paper we examined the serum levels of cytokines, growth factors, chemokines, as well as of other cancer and diabetes biomarkers in a discovery cohort of patients with T2D, chronic hepatitis C (CHC) and/or CHC-related HCC comparing them with a healthy control group to define a profile of proteins able to characterize these patients, and to recognize the association between diabetes and HCC. The results have evidenced that the serum levels of some proteins are significantly and differently up-regulated in all the patients but they increased still more when HCC develops on the background of T2D. Our results were verified also using a separate validation cohort. Furthermore, significant correlations between clinical and laboratory data characterizing the various stages of this complex disease, have been found. In overall, our results highlighted that a large and simple omics approach, such as that of the cytokinome analysis, supplemented by common biochemical and clinical data, can give a complete picture able to improve the prognosis of the various stages of the disease progression. We have also demonstrated by means of interactomic analysis that our experimental results correlate positively with the general metabolic picture that is emerging in the literature for this complex multifactorial disease.

The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.

• Chemokines
• Hepatocellular carcinoma
• Immune cells
• Chemokine receptors
• Inflammation
• Angiogenesis
• Tumor behaviors
• Treatments

• Cancer
• Free radicals
• HCV
• Inflammation
• NADPH oxidase
• Reactive oxygen species

• Animals
• Carcinoma, Hepatocellular/metabolism
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/metabolism
• Humans
• Liver Neoplasms/metabolism
• NADPH Oxidases/metabolism
• Oxidative Stress/physiology

• R01 CA158271 NCI NIH HHS
• R01CA158271 NCI NIH HHS

Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to pharmacological treatment, and a severe prognosis. Thus, the aim of this study was to investigate whether tacrolimus (FK506) has synergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Cell viability was analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Cell apoptosis was evaluated using Annexin V and Dead Cell assay. Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-1 and LC3B) were measured by western blotting analysis. Cytokines concentration in cellular supernatants after treatments was studied by Bio-Plex assay. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on tumor cells than single treatment. Moreover, our results showed that the mechanisms involved were (i) a strong cell apoptosis induction, (ii) contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii) downregulation of proinflammatory cytokines. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice models bearing HCC in order to see if this formulation could be useful in HCC treatment.

• hepatocellular carcinoma
• radical resection
• cytokines
• prognosis

• Adult
• Aged
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/pathology
• Cohort Studies
• Cytokines/biosynthesis
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/genetics
• Prognosis
• Proportional Hazards Models

The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.

• Hepatitis C virus
• Inflammation
• Cytokines
• Oxidative stress
• Hepatic disease
• Extra-hepatic diseases

AIM: To investigate the role of transforming growth factor-b (TGF-β) derived from regulatory T cells in metastasis of hepatocellular carcinoma.

METHODS: Forty-eight primary liver cancer patients without metastasis, 32 liver cancer patients with distant metastasis (17 cases of lung metastasis and 15 cases of brain metastasis), and 54 healthy subjects were included in this study. Serum concentrations of interleukin-10 (IL-10), IL-17A, tumor necrosis factor-α (TNF-α) and TGF-β were measured by ELISA. Levels of TGF-β in peripheral blood mononuclear cells (PBMCs) and regulatory T cells were determined by flow cytometry and RT-PCR, respectively.

RESULTS: Serum levels of TNF-α and TGF-β were significantly increased in liver cancer patients with metastasis compared with normal controls. Serum level of TGF-β was significantly higher in liver cancer patients with metastasis than in liver cancer without metastasis and normal controls (both P < 0.05). Furthermore, we confirmed that TGF-β in liver cancer patients with metastasis was derived from regulatory T cells by quantitative real-time PCR and flow cytometry.

CONCLUSION: TGF-β has a dual role in tumorigenesis; it acts as a tumor suppressor in early stage but promotes tumor cell invasion and metastasis in advanced stage. High level of TGF-β was found only in liver cancer patients with metastasis.

• Hepatocellular carcinoma
• Transforming growth factor-b
• Regulatory T cells

• Carcinoma, Hepatocellular/metabolism
• Cell Line, Tumor
• Cytokines/metabolism
• Glutathione Peroxidase/metabolism
• Hep G2 Cells
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Liver Neoplasms/metabolism
• Protein Binding
• Protein Interaction Mapping
• Protein Interaction Maps
• Selenium-Binding Proteins/metabolism
• Selenoproteins/metabolism
• Sodium Selenite/pharmacology
• Glutathione Peroxidase GPX1

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.

• Adipokines/blood
• Aged
• Chemokines/blood
• Cytokines/blood
• Diabetes Mellitus, Type 2/blood
• Female
• Hepatitis C, Chronic/blood
• Humans
• Liver Cirrhosis/blood
• Male
• Middle Aged

Hepatocellular carcinoma (HCC) is among the most aggressive and fatal cancers. Its treatment with conventional chemotherapeutic agents is inefficient, due to several side effects linked to impaired organ function typical of liver diseases. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies. The use of dietary antioxidants and micronutrients has been proposed for HCC successful management. The aim of this work was to test in vitro the effects of lipoic acid, caffeic acid and a new synthesized lipoyl-caffeic conjugate on human hepatoma cell lines in order to assess their effect on tumor cell growth. The results of cytotoxicity assays at different times showed that the cell viability was directly proportional to the molecule concentrations and incubation times. Moreover, to evaluate the pro- or anti-inflammatory effects of these molecules, the cytokine concentrations were evaluated in treated and untreated cellular supernatants. The obtained cytokine pattern showed that, at the increasing of three molecules concentrations, three pro-inflammatory cytokines such as IL-1β, IL-8 and TNF-α decreased whereas the anti-inflammatory cytokine such as IL-10 increased.

• Adiponectin/chemistry
• Adiponectin/metabolism
• Adiponectin/pharmacology
• Adiponectin/physiology
• Amino Acid Sequence
• Cells, Cultured
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Fibroblasts/physiology
• Gene Expression Regulation/drug effects
• Humans
• Membrane Proteins/chemistry
• Membrane Proteins/metabolism
• Membrane Proteins/physiology
• Models, Biological
• Models, Molecular
• Molecular Sequence Data
• Plant Proteins/chemistry
• Plant Proteins/metabolism
• Plant Proteins/pharmacology
• Plant Proteins/physiology
• Protein Multimerization/physiology
• Receptors, Adiponectin/chemistry
• Receptors, Adiponectin/metabolism
• Saccharomyces cerevisiae Proteins/chemistry
• Saccharomyces cerevisiae Proteins/metabolism
• Saccharomyces cerevisiae Proteins/physiology
• Seeds/chemistry
• Seeds/metabolism
• Sequence Homology
• Sequence Homology, Amino Acid
• Nicotiana/chemistry
• Nicotiana/metabolism

Epidemiological, preclinical and clinical studies demonstrated that chronic inflammation induced by hepatitis C virus (HCV) is crucial in hepatocellular carcinogenesis. The interaction between hepatocytes and microenvironment regards virus, inflammatory and immunocompetent cells, chemo- and cyto-kines, reactive oxygen species (ROS) and nitric oxide (NO), generating cell transformation. We suggest hepatocarcinoma (HCC) as a model in which the targeting of microenvironment determine neoplastic transformation. The present review focuses on: the role of inflammation in carcinogenesis, the clinical impact of HCC and the inadequacy of the actual therapy, the chemoprevention targeting the microenvironment.