An Abnormal Expression And Distribution Of Drosha In Precancerous Lesion And Gastric Adenocarcinoma

PART ONE EXPRESSION OF DROSHA IN THE TISSUES OF PRECANCEROUS LESION AND GASTRIC ADENOCARCINOMA AND ITS SIGNIFICANCEObjective:To study the expression and significance of Drosha protein in progression of gastric adenocarcinoma and investigate its effect on cell invasion of human gastric cancer SGC-7901 cells.Methods:1264 samples on tissue microarrays including 374 normal adjacent tissues,56 gastritis,34 precancerous lesions of gastric cancer (PLGC) and 800 gastric adenocarcinoma samples were detected for Drosha expression by immunohistochemistry staining and IPP software. The correlation between Drosha expression and clinicopathological characteristics was studied by χ2 test, and the prognostic value of Drosha for 219 gastric adenocarcinoma patients was assessed by Kaplan-Meier analysis. Drosha expression was knocked down by siRNA in SGC-7901 cells and then the invasive ability of cells was assessed by Matrigel Invasion Assay.Results:The low expression of Drosha in normal adjacent tissues (0.0879) and gastritis tissues (0.1062) were observed, and the expressions of Drosha were increased significantly in PLGC (0.4172, P<0.001) and gastric adenocarcinoma (0.2112, P<0.001) tissues. The expression of Drosha had a significant correlation with Laren classification (x2=79.089, P<0.001), tumor invasion depth (x 2=11.010,P=0.012), lymph node metastasis (χ2=9.075, P=0.028), tumor grade (x2=103.385, P<0.001) and tumor stage (x2=10.447, P=0.015). There was no significant difference in survival between the Drosha positive and negative patients groups (Log Rank=3.174, P=0.075). Cells invasion ability of SGC-7901 was enhanced after knocked-down Drosha expression.Conclusion:Drosha protein was greatly involved in the tumorigenesis of gastric adenocarcinoma and and the gastric cancer cells with low expression of Drosha had stronger capability for invasion and metastasis.PART TWO CYTOPLASMIC DROSHA IS ABERRANT IN PRECANCEROUS LESIONS OF GASTRIC CARCINOMA AND ITS LOSS CONFERS THE WORSE OUTCOME FOR CANCER PATIENTSObjective:The purpose of the present study was to assess the cytoplasmic and nuclear Drosha expression in carcinogenesis and progression of gastric cancer.Method:Drosha subcellular expression was investigated in a set of tissue microarrays including normal adjacent tissues (374), chronic gastritis (137), precancerous lesions (94) and gastric adenocarcinoma (829) by immunohistochemistry and in gastric cancer cell lines with different differentiation degree by immunofluorescence and western blot.Results:Cytoplasmic Drosha was gradually decreased along with tumor progression in both gastric cancer tissues and cell lines, and was negatively associated with tumor volume (p=0.003), invasion depth (p=0.007) and distant metastasis (p=0.027). The aberrant high level of cytoplasmic Drosha was firstly detected in intestinal metaplasia and dysplasia tissues. The Nuclear Drosha expression was sharply decreased in chronic gastritis and low expression of Drosha was maintained in precancerous lesions and gastric cancer. High level of cytoplasmic Drosha predicts a longer survival (LR=7.088, P=0.008) in gastric cancer patients.Conclusion:Our data provide novel knowledge for gastric cancer that cytoplasmic Drosha potentially plays a role in preventing carcinogenesis and tumor progression, and acts as an independent predictor of patient outcome.