Expression And Prognostic Pignificance Of FHIT And Ki-67 Proteins In Gallbladder Carcinoma

Objective:Gallbladder carcinoma(GBC)is a highly malignant neoplasm and difficulant in early diagnosis,so it represents a very poor prognosis.In order to enhance the rate of long-term survival and the quality of patients' rest life,we should not only try to rise the rate of early diagnosis of GBC,specify the operation,modify the treatment of radiochemotherapy after operation,but also identify the molecular changes involved in the pathogenesis of GBC.However, there is limited information about the molecular abnormalities involved in its pathogenesis.The Fragile Histidine Triad(FHIT)gene,encompassing the FRA3B fragile site at chromosome 3p14.2,is a candidate tumor suppressor gene in a variety of human malignancies.Recent studies have suggested that FHIT inactivation can be a consequence of defects in many tumors.Our objective was to examine the expression of FHIT and Ki-67 proteins in the GBCs,GBAs,and accompanying histologically normal epithelium form GBAs,and then analyze the correlation of the expression of two proteins with clinical features and patients' survival time,which may give some clues of the significance of FHIT and Ki-67 genes in the pathogenesis of GBC.The correlation of FHIT and Ki-67 was also analyzed.At last,on the terms of patients' survival time,we tried to find the independent affectoi of GBC.This study expected to provide some new molecular indicators for the pathogenesis,prognosis prediction and indication of clinical treatment of GBC,and offer some theoretical evidences for the early diagnosis, prevention and gene therapy of GBC.Methods.To elucidate the role of the FHIT abnormalities in the multistage sequential development of GBC,83 formalin-fixed paraffin-embedded invasive GBCs specimens,34 GBAs and accompanying histologically normal epithelium form GBAs(n=34)were examined by immunostaining for expression of FHIT and Ki-67 proteins.Then we analyzed the correlation of FHIT and Ki-67 proteins expression with clinicopathological findings via SPSS 13.0 statistical software.In addition,we used Cox proportion hazard regression model to elucidate the independent affectoi of prognosis of GBC.Results:(1)The positive rate in FHIT expression was noted in 59.7%(43/72)of the adenocarcinomas of gallbladder,++ and + were 12.5%,47.2%respectively. The rate of the GBAs was 79.4%,++ and + are 50.0%,29.4%respectively. And the rate of accompanying histologically normal epithelium form GBAs was 100%,++ and + were 94.1%,5.9%respectively.There was a significant difference among three tissues in the expression of FHIT(p＜0.01).And there were correlations between the expression of FHIT with CA199,adjacent liver invasion,TNM stage and metastasis(p＜0.05),but no correlation was found between expression of FHIT with gender,age,TB,differentiation degree,histological type,nerves invasion and lymph node metastasis (p＞0.05).(2)The positive rate in Ki-67 expression was noted in 84.7%(61/72)of the adenocarcinomas of gallbladder,++ and + are 36.1%,48.6%respectively. The rate of the GBAs was 22.2%,++ and + were 14.7%,32.4%respectively. And the rate of accompanying histologically normal epithelium form GBAs was 8.8%,++ and + were 0%,8.8%respectively.There was a significant difference among three tissues in the expression of Ki-67(p＜0.01).And there were correlations between the expression of Ki-67 with adjacent liver invasion,lymph node metastasis,TNM stage and metastasis(p＜0.05),but no correlation was found between expression of Ki-67 with gender,age,TB, CA199,differentiation degree,histological type,nerves invasion(p＞0.05).(3)FHIT protein expression was significantly associated with Ki-67 protein expression.Spearman relative rote was -0.621,p＜0.01.(4)Cox proportion hazard model multiplicity showed that lymph node metastasis,FHIT protein expression and modus operandi were independent prognosis affectoi of GBC,lymph node metastasis was risk factor,the other were protection factor.On the terms of relative risk,the influence of lymph node metastasis to prognosis was the strongest,the next was FHIT protein expression,the last one was modus operandi.Conclusions.These results indicated that reduced or lack of FHIT protein expression and enhanced Ki-67 expression might be involved in the pathogenesis of GBC,and examining the expression of FHIT and Ki-67 was significant for the early diagnosis of GBA canceration,evaluating the malignancy behavior of GBC. FHIT protein was independent affactoi of prognosis of GBC,reduced or lack of FHIT protein expression might promote the tumor proliferation directly or indirectly,and accelerate the carcinogenesis and development procedure of GBC via cell abnormity proliferation procedure(Ki-67).