Roles Of Adaptor Proteins Crk In The Malignant Behavior Of Human Serous Ovarian Cancer

Objective: To study the role of DOCK180/Rac1、SOS1/Ras signalingpathway downstream of adaptor protein Crk in the malignant behavior ofhuman serous ovarian cancer.Method:1. Rac1-GTP level and Ras-GTP level were measuredthrough GST-pull down assay in ovarian tissues from normal ovaries, benignovarian serous cystadenoma and serous epithelial ovarian cancer; Westernblot was used to detect the expression of DOCK180, Rac1, SOS1, and Ras,respectively. The association of DOCK180, Rac1and Rac1-GTP withclinical variables including FIGO stage, histological grade, the sensitivity tochemotherapy, and the outcome of cytoreduction was also analyzed.2.Comet assay was used to measure the apoptosis of DOCK180andRac1-knockdown SKOV3cells with or without CDDP treatment.3.Endogenous SOS1expression in human ovarian cancer cells(SKOV3、OVCAR3) was silenced by Lentivirus, and Cellomics assay wasperformed to detect the proliferation rates of the SOS1-knockdown cells.Result:Compared with benign serous tumor and normal ovarian tissues,Rac1and Ras activity were significantly increased in serous EOC （P<0.05);Meanwhile, significantly higher expression of DOCK180, Rac1,SOS1and Ras was detected in serous EOC, and we found the association ofhigher Rac1-GTP level and Rac1expression with suboptimal cytoreductivesurgery. Downregulating Rac1and DOCK180promotes apoptosis throughinducing DNA damage. Moreover, Rac1inhibition increased cisplatinsensitivity, but not DOCK180. Cellomics assay revealed SOS1had no effecton cell proliferation.Conclusion: DOCK180/Rac1signal downstream of adaptor proteinCrk plays an important role in the malignancy of human serous ovariancancer. The activated Rac1mediated through DOCK180/Rac1may haveassociation with clinical outcome in human serous ovarian cancer byinterfering the outcome of cytoreductive surgery. However, the exact role ofSOS1/Ras in regulating serous ovarian cancer needs further identifying.