transforming-growth-factor-beta and Hepatitis--Chronic

Hepatocellular carcinomas (HCCs) constitute a therapeutic challenge with mostly unfavorable outcome. This may reflect our incomplete understanding of disease pathogenesis, e.g. the elucidation of tumorigenic signaling pathways. Knowledge gathered hitherto focuses on genetic alterations that result in the loss of tumor suppressor functions as well as amplification and mutation of cancer genes. Further evidence points to a decisive role of cytostatic and apoptotic functions mediated on hepatocytes by transforming growth factor (TGF)-beta. These effects are critical for the control of liver mass with loss of TGF-beta activities resulting in hyperproliferative disorders and cancer. This concept is based on studies that describe a bipartite role of TGF-beta with tumor suppressor functions at early stages of liver damage and regeneration, whereas during cancer progression TGF-beta may turn from a tumor suppressor to a tumor promoter that exacerbates invasive and metastatic behavior. Consequently and most importantly, the oncogenic potential of recent therapeutic approaches against profibrogenic TGF-beta effects needs to be carefully delineated and a cancer therapy with specific targets disrupting the TGF-beta signaling cascade may be envisioned. In line with this concept, we and others found overexpression of TGF-beta antagonist Smad7 in the majority of HCC samples, providing a mechanism for hepatocytes to escape TGF-beta-dependent growth control in the process of cancerogenesis.

Topics: Carcinoma, Hepatocellular; Disease Progression; Hepatitis, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Transforming Growth Factor beta

Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-beta (TGF-beta) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-beta signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-beta signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-beta receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-beta. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (P<0.001), poor differentiation (P<0.001), portal vein invasion (P=0.002), intrahepatic metastasis (IM) (P<0.001), and shorter recurrence-free survival (P=0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC.

Topics: Aged; Carcinoma, Hepatocellular; Down-Regulation; Female; Hepatitis, Chronic; Hepatocytes; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasms; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

To explore the changes of cytokines including TNFalpha, TGFbeta1 and nitrogen monoxide, and endotoxin in the serum of chronic severe hepatitis after the treatment of ALSS, and to evaluate further the value of ALSS in the treatment of chronic severe hepatitis.. Forty two patients were screened. The changes of TNFalpha, TGFbeta1, nitrogen monoxide and endotoxin were detected respectively. The relationship between the cytokines and the severity and prognosis were further analyzed.. ALSS was effective to decrease the serum concentration of cytokines. TNFalpha dropped from (481.57+/-229.33) pg/ml to (156.46+/-78.12) pg/ml (P < 0.05). TGFbeta1 from (44.09+/-31.73) ng/ml to (27.77+/-23.28) ng/ml (P < 0.01), endotoxin from (1.05+/-0.37) Eu/ml to (0.28+/-0.22) Eu/ml (P < 0.001). NO from (71.15+/-33.09) micromol/L to (58.11+/-29.30) micromol/L (P < 0.001). Before the therapy endotoxin was related with TNFalpha and total bilirubin, while after the therapy, NO was related with protime and aminonemia.. High level of endotoxin and nitrogen monoxide in serum plays an important role in hepatocyte damage of chronic severe hepatitis. The changes of serum endotoxin TNFalpha, TGFbeta1 and nitrogen monoxide level in patients with chronic severe hepatitis can be used to judge the severity and prognosis of severe hepatitis. ALSS is a reliable hepatic support device for chronic severe hepatitis

Topics: Adult; Aged; Cytokines; Endotoxins; Female; Hepatitis, Chronic; Humans; Liver, Artificial; Male; Middle Aged; Nitric Oxide; Prognosis; Transforming Growth Factor beta

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.

Topics: Blotting, Northern; Collagenases; Decorin; DNA Primers; Extracellular Matrix Proteins; Female; Hepatitis, Chronic; Humans; Immunohistochemistry; Infant; Liver; Liver Cirrhosis; Middle Aged; Proteoglycans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Transforming Growth Factor beta1

To study the relationship between apoptosis of hepatocytes and liver fibrosis of chronic viral hepatitis (CH).. DNA fragmentation, one of the characteristic features of apoptosis, was detected by in situ terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and the expression of Fas, transforming growth factor beta 1 (TGF-beta 1) and Pre-collagen III peptide (P III P) in liver tissues were detected by immunohistochemistry. Soluble Fas (sFas) and TGF-beta 1 in serum were detected by ELISA.. The damage of DNA in hepatocytes of CH correlated closely with the expression of Fas and TGF-beta 1 in liver tissue and serum (r = 0.6129, 0.5368, 0.5564, 0.5996; P <0.05-0.01). In severe type CH and liver cirrhosis, the degree of liver fibrosis and the expression of P III P and TGF-beta 1 were higher than that in mild type and moderate type CH.. The sFas in serum may be one of the factors associated with the apoptosis. The apoptosis of hepatocytes correlated with liver fibrosis of CH and TGF-V beta 1 may play an important role between apoptosis and liver fibrosis.

Topics: Adolescent; Adult; Aged; Apoptosis; fas Receptor; Female; Hepatitis, Chronic; Hepatocytes; Humans; In Situ Nick-End Labeling; Liver Cirrhosis; Male; Middle Aged; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the relationship between expression of transforming growth factor beta 1(TGF beta 1), TGF beta 1 mRNA in liver tissue of patients with chronic viral hepatitis and degree of liver fibrosis.. TGF beta 1 protein was detected in 45 patients by immunohistochemistry and TGF beta 1 mRNA was detected in 21 of the 45 cases by in situ hybridization.. TGF beta 1 protein was 88.89%(40 of 45) positive in their liver tissues and was mainly distributed in interstitial cells, portal areas and the areas where fibrosis actively occurred, and the expression of TGF beta 1 protein was positively correlated with degree of liver fibrosis(r = 0.73, P < 0.05). TGF beta 1 mRNA was 80.95%(19 of 21)positive in their liver tissues. Positive stains were not only detected in sinusoidal cells and mononuclear cells, but also in some parenchymal cells.. The expression of TGF beta 1 correlated closely with liver fibrosis of viral hepatitis. Not only interstitial cells, but also parenchymal cells in liver might participate in the fibrogenisis by producing TGF beta 1.

Topics: Adolescent; Adult; Aged; Female; Hepatitis, Chronic; Hepatitis, Viral, Human; Humans; Male; Middle Aged; RNA, Messenger; Transforming Growth Factor beta

Topics: Hepatitis C; Hepatitis, Chronic; Humans; Liver Cirrhosis; Transforming Growth Factor beta

In a semiquantitative assessment of the expression of transforming growth factor (TGF) beta 1 in liver biopsy specimens from patients with chronic hepatitis C, treatment with interferon alfa-2b (3 million units (MU) three times weekly) decreased the expression of TGF beta 1 in six of seven patients. The reduction in TGF beta 1 correlated significantly with the scores for inflammation (p < 0.05) and necrosis (p < 0.05), but not with the alanine aminotransferase activities (p = 0.36) or the score for fibrosis (p = 0.86).

Topics: Adult; Aged; Female; Hepatitis C; Hepatitis, Chronic; Humans; Immunohistochemistry; Interferon alpha-2; Interferon-alpha; Liver; Male; Middle Aged; Recombinant Proteins; Time Factors; Transforming Growth Factor beta