The Role Of PI3K-Akt Pathway In Hepatoblastoma And Evaluation Of Prognostic Risk Factors Of Patients With Hepatoblastoma

Part 1:The role of PI3K-Akt Pathway in HepatoblastomaBackgroundHepatoblastoma represents the most frequent malignant liver tumor in childhood. Due to the combination of liver resection surgery and chemotherapy, and the development of individual measures of preoperative and postoperative chemotherapy in the past 20 years, the prognosis of children with hepatoblastoma has been greatly improved. The PI3K-Akt pathway is a classic anti-apoptotic, pro-survival signal transduction pathway in tumorigenesis, proliferation, invasion and metastasis of various tumors.ObjectiveThe current study was done to analyze the role of PI3K-Akt signaling in hepatoblastoma cell lines and tumor samples. Understanding the importance of PI3K-Akt pathway in hepatoblastoma could provide a theoretical basis for the subsequent development of the treatment of hepatoblastoma targeted drugs by inhibiting this pathway.MethodsBy differences in gene expression screening we found that PI3K-Akt pathway-related factors were over-expression in tumor tissues, including PI3K, Akt, PKC, PKB and GSK-3 etc. In vitro, two hepatoblastoma cell lines treated with the PI3K inhibitor LY294002 were analyzed for PI3K and Akt. RT-PCR was used to detect differential expression of PI3K mRNA in tumor tissues and adjacent tissues. Western blot was used to detect the proteins of PI3K, p-Akt (Ser473) and the total Akt.ResultsIn the study, the hepatoblastoma cell lines HUH6 and HepG2 were cultured with increasing concentrations of the PI3K inhibitor LY294002. Both cell lines showed a dosedependent growth inhibition in MTT assays. PI3K signaling inhibition in hepatoblastoma cell lines was associated with reduced PI3K and p-Akt(Ser473) (p<0.001). PI3K miRNA expression in tumor tissue was significantly higher than the adjacent tissues; the expression of PI3K and p-Akt (Ser473) protein in tumor tissues was significantly higher than that of the adjacent tissues. The total Akt and β-actin was no significant difference in the two groups of patients.ConclusionsActivation of PI3K-Akt pathway can result in hepatoblastoma tumor cell proliferation. The pathway related factors in tumor tissues were significantly higher than that in the adjacent tissues, which suggesting that PI3K-Akt pathway plays an important role in the development of hepatoblastoma.Part 2:Evaluation of Prognostic Risk Factors of Patients with HepatoblastomaBackgroundHepatoblastoma represents the most frequent malignant liver tumor in childhood. Children with HB respond well to chemotherapy and have a high cure rate (3-year overall survival (OS):70%). Although children with HB is generally thought to have a good prognosis, the survival outcomes following surgical resection may vary, as several factors are associated with the prognosis of HB。ObjectiveThe aim of this study is to investigate and identify the predictors associated with the prognosis of patients with hepatoblastoma (HB) and detect the relationship between the various risk factors.MethodsWe retrospectively reviewed 176 children with HB managed in our institution between January 1st,2001 and September 30th,2014. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazards models.ResultsFor the entire cohort of 176 patients, the overall median survival was 80.4 months, and the 5-year EFS and OS rates were 54.6% and 66.7%. The prognosis of children with HB were associated with AFP levels, multifocality, PRETEXT stage, metastasis and pathological type. Multivariate analysis showed that AFP levels (HR:2.567, P=0.014) multifocality (HR:2.187, P=0.028), PRETEXT stage (HR:2.254, P=0.005), metastasis (HR:1.912, P=0.028) were independent risk factors. Different histological type groups interacted with each other and after introduction of multivariate Cox model by each, Pure fetal histology type(HR:2.752, P= 0.021) was an independent risk factor related with EFS.ConclusionsWe have confirmed the HB prognostic factors associated with survival in the Asian population and found histological types of tumors were interacted with other factors and further influence of pathological type for prognostic varied in the presence of various risk factors.