| Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with an increased morbidity recently, and about 50% cases occur in china. Also, HCC accounts for the third leading cause of cancer-related deaths worldwide and the second in china. The predominant mechanisms leading to HCC is still poorly understood, what we know is that some factors are associated with an increased risk of development of the cancer, such as hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin, vinyl chloride, and alcoholic liver disease. How to reduce the increased morbidity of HCC and achieve to prevention of this malignancy is an urgent strategic task facing us at present.HCC have an interesting epidemiologic feature : gender disparity in morbidity. Statistics show that males have higher liver cancer rates than females with male:female ratios usually averaging between 2:1 and 4:1 or even 11:1 in HCC associated with cirrhosis, and about 35.2/100,000 in men and 13.3/100,000 in women for china incidence of HCC. The phenomenon of gender disparity in HCC got attention very early, and the explanation for this disparity are mainly social and environmental factors such as a higher prevalence of persistent HBV or HCV infection, alcohol abuse, and smoking in men than in women in previously. But genetic and hormonal factors are getting more and more attention. Accumulating evidence has indicated that androgen may play some roles in promotion of hepatocarcinogenesis while estrogens may have a somewhat protective role against the development of HCC. However, there is not a definitive conclusion for their relationship and the mechanisms involved in it are still not clear. On the premise of not appreciable impacting the sexual function and secondary sex characters of patient, using expression changes of sex hormone and it's receptor's for effective intervention of the initiation and development of HCC was always a possible breakthrough research.Based on above knowledges, in this study, we starts from the issue of gender disparity in morbidity of HCC, then using our established HCC rat model by administration of DEN and NMOR, to explore the influence of sex hormone on HCC gender disparity and in depth analyzing the mechanism of estrogen suppresses hepatocarcinogenesis, trying to thrown new light upon mechanism of protcetive role of estrogen in hepatocarcinogenesis in theory and provide some essential information for the clinical prevention and management of HCC.In our study, we first evaluated the stepwise progression in a rat model for hepatocellular carcinoma induced by diethylnitrosamine and N-nitrosomorpholine and investigate the influrence of sex hormone on this process, then proving our hypothesis in protective effects of physiological doses of estrogen during hepatocarcinogenesis, and in final analyzing the mechanism of protcetive role of estrogen in hepatocarcinogenesis from protein and nucleic acid by using ELISA, IHC, RT-PCR.The results of this study indicate:1.We found that our established HCC rat model induced by DEN and NMOR represents a classic case of inflammation-linked cancer, can realistic reflection of the stepwise progression in hepatocarcinogenesis, or, named"hepatitis-cirrhosis-HCC"trilogy, can be a useful tool for investigating the initiation, development and metastasis of HCC. Also, we further confirmed a sex dimorphism in HCC development and indicating the protcetive role of estrogen in hepatocarcinogenesis. 2. We showed that physiological doses of estrogen can significant inhibit the initiation, development and metastasis of chemically induced inflammation-linked rat HCC.3. Our study showed that estrogen can modulating the inflammatory hepatic and tumor microenvironment with one of the main mechanism by suppressing HGF and IL-6 production, and this may be response to gender differences that are detectable in the occurrence of HCC. |
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