Eps8 decreases chemosensitivity and affects survival of cervical cancer patients.
The oncoprotein Eps8 facilitates proliferation in fibroblasts and colon cancer cells. However, its role in human cervical cancer is unclear. By immunohistochemical staining and Western blotting, aberrant Eps8 expression was observed in cervical carcinoma compared with normal cervical epithelial cells. Clinicopathologic analysis of 45 patients indicated that Eps8 expression was associated with parametrium invasion and lymph node metastasis, two major poor prognostic factors for early-stage cervical cancer. Kaplan-Meier analysis of cervical cancer specimens also indicated an inverse relationship between the level of Eps8 and the patients' survival rate. Using small interfering RNA of eps8, we observed reduced proliferation and tumorigenesis in Eps8-attenuated HeLa and SiHa cells cultured in dishes or inoculated in mice. Furthermore, diminished Eps8 impeded G(1)-phase progression in HeLa and SiHa cells that might be attributable to reduced expression of cyclins D1, D3, and E, elevated accumulation of p53 and its downstream target p21(Waf1/Cip1), and suppressed hyperphosphorylation of retinoblastoma. Alteration of these cell cycle-related proteins could be reversed by ectopic Eps8, implicating that the effect of Eps8 on the mentioned cell cycle modulators was specific. Notably, the augmented expression of p53 by diminished Eps8 was at least due to its decreased turnover rate. Concurrent with p53 up-regulation and the decrement of Src and AKT activity, Eps8-attenuated HeLa and SiHa cells exhibited increased chemosensitivity to cisplatin and paclitaxel. Together, our findings implicate the involvement of Eps8 in chemoresistance and show its importance in prognosis of cervical cancer patients.
Institute of Medical Science, China Medical University, Taichung 40402, Taiwan, People's Republic of China.
Yun-Ju
YJ
Chen
Meng-Ru
MR
Shen
Yen-Jen
YJ
Chen
Ming-Chei
MC
Maa
Tzeng-Horng
TH
Leu
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D017239:Paclitaxel / Q000494:pharmacology; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489989:EPS8 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D002945:Cisplatin