Mechanistic study of interaction between IL-22 and HCV core protein in the development of hepatocellular carcinoma among liver transplant recipients.

BACKGROUND: Hepatitis C virus (HCV) infects more than 170 million people worldwide that represents a major threat to global public health. Several viruses including HCV have developed mechanisms against the cellular responses essentially "hijacking" the antiviral responses generated against it. Interleukin 22 activated JAK-STAT pathways are responsible for several functions including liver regeneration, antiviral responses and cell cycle regulation. OBJECTIVES: Present study aims to un-reveal the speculated role of HCV core protein in perturbing IL-22 mediated JAK-STAT pathway. Principally investigating through interaction with IL-22 and SOCS-3 proteins. PATIENTS AND METHODOLOGY: Total 36 liver transplant patients were enrolled in the study. Out of which 24 were found HCV + ve. Immunohistochemistry (IHC) based qualitative expression analysis of IL-22, SOCS-3 and HCV core protein was carried out. Microscopy was performed for detection and visualization of immunostained liver tissues and biopsies. RESULTS: Hepatic expression of IL-22, HCV core protein and SOCS-3 showed that SOCS-3 expression levels were considerably high compared to HCV core and IL-22 protein. IL-22's moderate to high expression was found in 70% of the liver transplant patient sample. Total 87% patients showed moderate to high SOCS-3 expression. However, the overall expression of HCV core was stronger in 87% of cirrhotic patients and 14% in HCC patients. Suggesting the presence of HCV core protein clearly impacted the IL-22 mediated cellular signaling (JAK-STAT pathway leading towards hepatocarcinogenesis. CONCLUSION: HCV core and IL-22 and SOCS-3 molecules are found to be correlated statistically under this study. Concluded from this study that HCV core protein plays a potential role in diverging the hepatocytes from normal to carcinogenic. One cell signaling path cannot decide, the direct role of a single viral protein in developing viral induced hepatocarcinogenesis. Interpreting the complex network of cell signaling involved in HCC development is impractical to study under single study. That is why step by step unmasking the interactive role of few molecules under single study is the ideal way to resolve the impact of viral proteins on cell signaling. SOCS-3 is mediator for dysregulating IL-22 mediated liver regenerative pathway. Moreover, SOCS-3 and STAT-3 molecules are proposed to be a potential therapeutic target for managing HCC progression.

IL-22 in hepatocyte's survival of Pakistani patients with end stage liver disease: an insight into IL 22 mediated hepato-regenerative pathway.

Hepatitis is the principal cause of hepatocellular carcinoma (HCC) and decompensated cirrhosis. HCC is amongst the leading causes of deaths worldwide. Current therapeutic options have proven to be unsuccessful in treating this disease due to multifactorial nature of the disease. The present study was designed to investigate the role of IL-22 mediated survival of hepatocytes during cirrhosis and HCC. Resected/explanted liver tissue samples of patients with End Stage Liver Disease were obtained from Hepato-Pancreato-Biliary Liver Transplant Unit of Sheikh Zayed Hospital, Lahore, Pakistan. Qualitative expression of IL-22, SOCS3, and IL-22 induced anti-apoptotic protein, B-cell lymphoma extra-large (Bcl-xL), were evaluated by Immunohistochemical analysis (IHC). The IHC analysis revealed significantly high expression of IL-22, SOCS3, and Bcl-xL within explanted livers of HCC patients. Overall, the expression of SOCS3 was higher than any other protein, and the expression of all proteins showed significant variation in different group of patients based on clincopathological features. The results of the current study indicated that IL-22 mediated JAK-STAT pathway i.e. liver regeneration and healing is dependent on the disease progression and type of agent responsible for causing the infection in the first place. However, quantitative analysis of these factors in future can provide further evidence of the role of this pathway in HCC for development of anti-HCC therapies.

Purinoceptor expression in hepatocellular virus (HCV)-induced and non-HCV hepatocellular carcinoma: an insight into the proviral role of the P2X4 receptor.

The basic idea behind this study was to discover the association and prevalence of purinoceptors in hepatitis C virus (HCV) and non-HCV hepatocellular carcinoma (HCC). Immunohistochemistry was performed to study the expression of P2X4 and P2X7 receptors on ex-planted liver tissue samples that were collected from HCC patients. Antibodies specific for the P2X4 and P2X7 receptors were used to target the specific receptors and secondary antibody was used with 3,3'-diaminobenzidine (DAB) detection system to visualize the color change in case of any positive expression There was a substantial increase in P2X4 receptor expression in HCV induced HCC as compared to non-HCV HCC. Surprisingly, there was no increase in the P2X7 receptor expression in both HCV HCC and non-HCV HCC. We conclude that P2X4 receptor expression was significant in the presence of HCV HCC. This may confirms the potential role of P2X4 receptor in the presence of virus in liver pathology. However insignificant expression of P2X7 receptor may avert our attention towards understanding the role of this receptor in pro-inflammatory and immune responses.

IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a growing concern all over the world. With the number of patients rising exponentially with each passing day, HCC is a problem that needs immediate attention. Currently, available treatment strategies focus on controlling the damage after the development of HCC. The options available from chemo- and radio-embolization to surgical resection and transplantation are not efficacious as required due to the complex nature of the disease. Liver regeneration and tissue healing are the subject of great interest today. Interleukin-22 (IL-22) is a cytokine with the ability to regenerate and therefore reverse the injuries caused by a wide range of agents. IL-22 acts via STAT molecule and controls the activity of a wide variety of cell survival and proliferation genes. Experimental data has given a positive insight into the role of IL-22 in inhibition of viral and alcohol-induced hepatocellular carcinoma. A further insight into the nature of IL-22 and the factors that can be manipulated in controlling the activity of IL-22 can help to counter the menace caused by the devastating effects of HCC.