الفهرس 
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Abstract
In Egypt, hepatocellular carcinoma (HCC) is a common malignancy, it ranks the second and sixth most common cancer among men and women, respectively. One of the major causes of HCC is hepatitis C virus (HCV) which is reported to infect about 10-14% of Egypt’s population and is considered to be the second most common cause of HCC.
Abundant evidence has revealed that autophagy is involved in the pathogenesis of various diseases including liver diseases. Autophagy has emerged as a cellular pathway, playing a role in different aspects of HCV infection course. Meanwhile, it has been suggested that tumor cells rely on autophagy for survival in HCC, although it is still controversial whether autophagy serves as an anti-cancer or pro-cancer mechanism.
Importantly, autophagy has been linked to other cell death pathways e.g., apoptosis and necrosis. Accumulating evidence reveals that autophagy and apoptosis can cooperate, antagonize or assist each other, thus influencing differentially the fate of the cell. It has been delineated several pathways that mediate the complex interplay between autophagy and apoptosis providing mechanistic insight into the network that regulates both processes.
Moreover, vitamin D and autophagy are associated with innate immunity, inflammatory bowel diseases, infection, and cancer.
Accordingly, the present study was undertaken to investigate, on one hand, the cross-talk between autophagy and apoptosis. On other hand, the association between both of autophagy and apoptosis and vitamin D and its receptor in HCV viral infection and its implication in the progression into HCC. The objectives of the present study were approached by assessing serum levels of LC3; marker of autophagy, caspase-3; marker of apoptosis, vitamin D3 and vitamin D receptor (VDR) in healthy subjects as well as HCV and HCV-HCC patients.
In both HCV and HCV-HCC patients groups, a significant increase in serum aminotransferase (AST and ALT) and serum bilirubin level has been observed. Also, a significant reduction in serum albumin level was observed in both groups. Collectively, the results may reveal the hepatic dysfunction in HCV patients with or without HCC.
In HCV and HCV-HCC patients groups, the results of the present study revealed a significant reduction in the serum LC3 level. Thus, the present study may point out the inhibition of autophagy in HCV patients with or without HCC and degree of autophagy inhibition was more pronounced in patients with HCV-HCC than HCV patients.
On the other hand, the results of the present study revealed a significant reduction the serum caspase-3 which may reflect the inhibition of host-mediated apoptosis. During HCV infection, apoptosis can be induced as a cellular defense mechanism mediated indirectly by immune attack of infected cells or directly by viral infection. However, HCV has evolved several ways to block host-mediated apoptosis. Accumulating evidence suggests that HCV proteins have the ability to inhibit host cell apoptosis. Several studies have been under taken to explain the pro- and anti-apoptotic role HCV infection which result in a circle of hepatocyte damage and repair, which is the hallmark of HCV infection that might progress to HCC.
In agreement with results of present study, several studies have demonstrated the deficiency of vitamin D is very common in patients with chronic hepatitis C virus infection. Thus, chronic hepatitis C patients are characterized by a high prevalence of vitamin D deficiency compared with a control population, and an independent inverse relationship was described between vitamin D serum levels and liver fibrosis severity. On the other hand, several studies have reported low vitamin D receptor expression in chronic hepatitis C. In the line of these studies, the results of the present study revealed a significant reduction in serum level of VDR in HCV patients with or without HCC. Thus, the reduction in both serum levels of vitamin D and vitamin D receptor may reflect the inefficacy vitamin D/VDR signaling pathway. Furthermore, the results of the present study may point out to the crucial role VDR in vitamin D-mediated biochemical process including autophagy and apoptosis. Evidently, the results of the present study revealed a strong positive correlation between VDR and both of LC3 and caspaase-3. Such correlations were not found between vitamin D and both biochemical markers referring to the importance of VDR in such pivotal biochemical processes.
Accordingly, the present study may lead to the suggestion that autophagy and apoptosis processes are modulated throughout the course of HCV infection in favor of virus persistence and survival. Moreover, the molecular mechanisms of anti-autophagy and anti-apoptotic activity of HCV might play a pivotal role in regulation of hepatic cell growth and development of HCV-HCC and probably enabling the survival and growth of neoplastic hepatocytes. The dysfunction of vitamin D/VDR axis which modulates both of autophagy and apoptois in HCV infection may point out to its involvement and implication in the pathogenesis of HCV infection and the development of HCV related HCC. Vitamin D receptor may play a crucial role in vitamin D regulation of autophagy and apoptosis during the course of HCV. Therefore, impairment in the expression of VDR, indicated by its serum level, may comprise in vitamin D biochemical function as anti-inflammatory, anti-proliferative and anti-tumorgenesis. Therefore, supplementation with vitamin D may not be the only solution to restore the vital biological functions of vitamin D but VDR-targeted therapy may be of great importance with this respect