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Expression of Gadd45α/γ Protein in Human Hepatocellular Carcinoma and the Related Signal Transduction Pathways in Gadd45α-induced Growth Suppression of Hepatoma Cells

Author: ZhuNa
Tutor: SunLuHong
School: Nanjing Medical University
Course: Immunology
Keywords: Hepatocellular carcinoma Gadd45α protein Gadd45γ protein HepG2 G2 / M
CLC: R735.7
Type: Master's thesis
Year: 2008
Downloads: 91
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Abstract


Hepatocellular carcinoma (HCC) is one of our common malignant tumor of serious harm to human life, the incidence of malignancies in second place. , Hepatocellular carcinoma (hepatocellularcarcinoma HCC) is the most important type of organization. Explore the molecular mechanisms of abnormal gene expression in HCC tissue has important theoretical and practical significance for the understanding of its occurrence, the development process as well as auxiliary diagnosis and treatment. The Gadd45 gene families in the study tumorigenesis, development and transfer process newly discovered gene family, the family members are mainly including Gadd45a, Gadd45p, and Gadd45y. Available information indicates that the gene family play an important role in the regulation of cell cycle process, but its impact on the human hepatoma cell line HepG2 cell cycle and the specific mechanism is not clear, therefore, this study Gadd45α / gamma in HCC expression and Gadd45α inhibits liver cancer cell growth signaling pathway was discussed. Gamma in HCC first part Gadd45α / expression and cell cycle of human hepatoma cell line HepG2 Objective: detection Gadd45α / gamma protein expression in hepatocellular carcinoma, and to evaluate its impact on the human hepatoma cell line HepG2 cell cycle. Methods: randomly selected clinical HCC samples 50 cases, the use of immunohistochemistry to detect the expression level of Gadd45α / gamma protein in 50 cases of hepatocellular carcinoma and adjacent tissues and analysis of clinical significance; vitro cultured human hepatoma HepG2 cells were transfected plasmid pCMV-Tag2B, the pCMV-Tag2B-of Gadd45a and the pCMV-Tag2B-Gadd45γ use flow cytometry Gadd45α / gamma cell cycle distribution. Results: (1) of Gadd45a protein in 50 cases of hepatocellular carcinoma positive rate was 58.0% (29/50), adjacent tissues positive rate was 62.0% (31/50), the difference was not statistically significant; Gadd45γ protein expression in HCC was 30.0% (15/50) in adjacent tissue expression rate was 86.0% (43/50), both of which have more significant difference (p <0.01). (2) Gadd45α / gamma protein expression positive rate of liver cancer differentiation, well-differentiated carcinoma positive rate (84.2%, 57.9%) was significantly higher than the positive rate in poorly differentiated carcinoma (41.9%, 12.9%) ; significant difference (p <0.05) between the two, Gadd45α / gamma protein expression positive rate of gender, age, and lymph node metastasis obvious correlation (p> 0.05). (3) the the plasmid pCMV the-Tag2B-Gadd45α / gamma were transfected into human HepG2 cells induces cell cycle G2 / M phase arrest, the pCMV-tag2B-Gadd45α (G2 / M phase cell ratio to 0.31 ± 0.03) induced block extent than the the pCMV-Tag2B-Gadd45γ (G2 / M phase fraction to 0.21 ± 0.03) induced block more obvious. Conclusion: Gadd45α / gamma protein expression may be associated with the pathological type of liver cancer, development and transfer process there is a close relationship, compared with Gadd45γ Gadd45α transfer process of liver cancer may play a more important role, and for the liver cancer gene therapy provides a new molecular targets. The second part of the Gadd45a apoptosis of human hepatoma cells in G2 / M phase arrest signal transduction pathway research purposes: to explore Gadd45α inhibit the growth of liver cancer cells may be involved in signal transduction pathway, preliminary theoretical basis for the study of liver cancer cell growth inhibitory gene. Methods: In vitro cultured human hepatoma cells HepG2 cells were transfected plasmid pCMY-Tag2B-Gadd45α the pCMV-Tag2B to western blot was used to detect changes in the expression of the Gadd45α and its downstream gene p38, p-p38, JNK and p-JNK; then given signaling pathway inhibitor (SB203580 and SP600125) specifically block the phosphorylation of p38 and JNK, and then the use of flow cytometry and compare the cell cycle, and then analyzes Gadd45α induced HepG2 cells in the G2 / M phase may be involved in signaling pathways. Results: (1) the the plasmid pCMV-Tag2B was-Gadd45α transfection in human hepatoma cells HepG2 after 48 h, Gadd45α protein expression peak of 0.68 ± 0.02, its downstream gene p38 (0.94 ± 0.01) and JNK phosphorylation (0.77 ± 0.04) compared to the level of the control group (0.58 ± 0.02,0.50 ± 0.02) were significantly increased. (2) the use of a specific inhibitor of the elevated expression of p38 and JNK phosphorylation levels decreased to 0.56 ± 0.02 and 0.53 ± 0.03, reached the level of phosphorylation of the control group (0.58 ± 0.02,0.50 ± 0.02), but the cells still showed G2 / M block, the block than non-inhibitor group was significantly weakened. Conclusion: The over-expression in HepG2 cells Gadd45a protein can activate Gadd45α-P38, and Gadd45α-JNK signal transduction pathway; Gadd45α-P38 and Gadd45α, JNK pathway in liver cancer cells the Gadd45α induced G2 / M phase arrest.

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