| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 104 === Epithelial ovarian carcinoma has the highest mortality rate among gynecologic malignancies and is an important disease in the field. Early diagnosis is difficult due to the lack of obvious initial symptoms, therefore ovarian cancer patients are usually diagnosed at advanced stage. Current treatments include debulking surgery and adjuvant chemotherapy with the regimen of platinum and paclitaxel which have a response rate of 80% for all patients and 40-60% for advanced-staged patients, but they usually relapse after initial response and ultimately die of recurrence. Chemo-resistance is an obstacle in the managements of epithelial ovarian cancer. A clinical prognostic factor reflecting the possible mechanisms and biological characteristics of oncogenesis or chemo-resistance may be helpful in the development of new therapeutic strategies. In the first study, we conducted the nationwide database analysis through Taiwan cancer registry system from 1979 to 2008 to evaluate the pattern, incidence and prognosis of epithelial ovarian carcinomas in the last three decades. The age-specific incidence rates increased especially in serous, endometrioid and clear cell carcinoma, and the age of diagnosis decreased from sixty to fifty years old in the three decades. Patients with mucinous, endometrioid, or clear cell carcinoma had better long-term survival than patients with serous carcinoma (log rank test, p<0.001). Patients with undifferentiated carcinoma or carcinosarcoma had poorer survival than those with serous carcinoma (log rank test, p<0.001). The mortality risk decreased from the period of 1996-1999 (hazard ratio [HR]: 0.90, p=0.054) to the period after 2000 (HR: 0.74, p<0.001) as compared with that from the period of 1991-1995. In the second study, we reported a new cell line, CA5171, derived from a chemotherapy-naive, epithelial ovarian carcinoma patient. The CA5171 cells presented with cobblestone morphology and a doubling time of 24 hours. Gene mutation analysis showed that the cells belonged to the type II ovarian cancer pathway with mutations of PIK3CA, PTEN and TP53. Single-nucleotide polymorphism array analysis showed no homozygous gene deletion; however, several loci of gene copy number gains were noted in chromosome 1, 2, 5, 9, 10, 12, 15, 16, 20 and X. The in vitro and in vivo experiments showed that the cells were sensitive to paclitaxel and doxorubicin, but resistant to cisplatin. The cells also presented epithelial–mesenchymal transition properties that may have been related to their invasion and migration potential. The CA5171 cells show the potential as a new cell line for studies on epithelial ovarian carcinoma. In the third study, the association of CHI3L1 expression and clinical outcomes of epithelial ovarian carcinoma patients were investigated. The expression of CHI3L1 was also higher in patients with a serous histological type, advanced stage, and chemo-resistance. Patients with high CHI3L1 expression had a shorter progression free survival (log rank test, p < 0.001) and overall survival (log rank test, p < 0.001). Patients with high CHI3L1 expression also had a high risk of recurrence (HR: 2.91, 95% CI: 1.89−4.48, p < 0.001) and death (HR: 4.03, 95% CI: 2.37−6.87, p < 0.001). In vitro studies showed that CHI3L1 up-regulated the expression of anti-apoptotic Mcl-1 protein and hampered paclitaxel-induced apoptosis of ovarian cancer cells. These results suggest that CHI3L1 shows potential as a prognostic biomarker for epithelial ovarian carcinoma. In summary, the nationwide database analysis provided the long-term epidemiological information of epithelial ovarian cancer in Taiwan. The CA5171 cell line had the potential as a new tool for studies on epithelial ovarian carcinoma. The CHI3L1 expression of ovarian cancer tissue was a potential marker for epithelial ovarian cancer patients.
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