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Abstract
Introduction Epithelial ovarian cancer (EOC) frequently recurs and develops chemo-resistance, resulting in cancer mortality. TIMP3 has been described as a tumor suppressor in several human malignancies, but limited scientific literature focus on the role of TIMP3 in regulating EOC progression or chemoresistance.
Methods Both progression-free survival (PFS) and overall survival (OS), stratified by TIMP3 level were estimated using the Kaplan-Meier method and compared using log-rank tests. To increase the expression level of TIMP3 in A2780CP70 cells, the cells were transfected with the TIMP3 expression vector. The migration and invasion abilities of the transfected cells were estimated using transwell assay. The sensitivity of transfected cells to paclitaxel and apoptotic population were evaluated by MTT assay and flow cytometry assay, respectively. A human apoptotic array was used to screen for changes in apoptosis-related proteins.
Results Patients with TIMP3-overexpressed tumor had favorable long-term PFS (p <0.001) and OS (p <0.001) (figure 1A). A significant reduction in cell migration and invasion capacities was observed in TIMP3-overexpressed A2780CP70 cells (figure 1B and 1C). TIMP3 contributed to affect sensitivity of A2780CP70 cells to paclitaxel (figure 2A), rather than cisplatin. Representative apoptotic profiles showed that increased apoptotic cell populations were more apparent in TIMP3-overexpressed A2780CP70 cells, treated with paclitaxel for 48 hours when compared to its parental cells which is possibly related to down-regulation of cIAP-1, survivin, CLSPN, and HSP-27 (figure 2B and 2C).
Conclusion/Implications Overexpression of TIMP3 inhibited EOC aggressiveness of A2780CP70, and increased paclitaxel sensitivity. TIMP3 might be a potential target for EOC treatment.
