Eps8 decreases chemosensitivity and affects survival of cervical cancer patients

Abstract

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. [Mol Cancer Ther 2008;7(6):1376 -85]

Eps8 Protein Facilitates Phagocytosis by Increasing TLR4-MyD88 Protein Interaction in Lipopolysaccharide-stimulated Macrophages

“…Reduced activity of Src and FAK in Eps8-attenuated RAW cells suggested that Eps8 might directly regulate the activity of both kinases as reported previously (22,42). Given that cytochalasin B exerted no effect on the activity of Src and FAK but significantly inhibited LPS-elicited Eps8 expression as well as phagocytosis of GFP-E. coli (Fig.…”

The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation

“…Overexpression of Eps8 conferred the ability of fibroblasts to form focus in culture dish and grow tumor in mice (Maa et al, 2001), corroborating the oncogenic potential of Eps8. In agreement, Eps8 attenua tion retarded cellular growth in IV5 cells (Leu et al, 2004) and human cancer cells (Maa et al, 2007;Chen et al, 2008;Xu et al, 2009). Remarkably, Eps8 is also a prognostic factor for cervical cancer.…”

“…Unlike the involvement of Eps8 in cytoskeletal reorganization is gradually disclosed, the implication of Eps8 in tumorigenesis is well established. Elevated expression of Eps8 was observed in v-Src transformed (IV5) cells (Gallo et al, 1997;Maa et al, 1999), and in a variety of human tumors including colorectal (Maa et al, 2007), cervical (Chen et al, 2008), pituitary (Xu et al, 2009) and oral cancers (Yap et al, 2009). Overexpression of Eps8 conferred the ability of fibroblasts to form focus in culture dish and grow tumor in mice (Maa et al, 2001), corroborating the oncogenic potential of Eps8.…”

“…Remarkably, Eps8 is also a prognostic factor for cervical cancer. This can be evidenced by the observation that early-stage cervical cancer patients with higher Eps8 expression tend to have parametrial invasion, lymph node metastasis and decreased survival rate (Chen et al, 2008).…”

Human Intersectin 2 (ITSN2) binds to Eps8 protein and enhances its degradation

“…Eps8 enhances EGF-dependent mitogenic signals and leads to malignant transformation (1,20). Eps8 increases cell growth and motility, by the up-regulation of FOXM1, FAK, MMP-9, ERK, Akt, cyclins D1, D3, and E, the down-regulation of P53 and p21Waf1/Cip1 in squamous cell carcinoma, pancreatic cancer, cervical cancer, colon cancer, pituitary tumors and esophageal carcinomas (4,5,(21)(22)(23)(24)(25)(26). Eps8 is an important signal molecule, we demonstrated here that ITSN2 and Eps8 interact in vivo, and the interaction between both proteins results in the decrease of Eps8 proteins.…”