Eps8 decreases chemosensitivity and affects survival of cervical cancer patients

Yun Ju Chen, Meng-Ru Shen, Yen Jen Chen, Ming Chei Maa, Tzeng-Horng Leu

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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 G1-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 p21Waf1/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.

Original languageEnglish
Pages (from-to)1376-1385
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number6
DOIs
Publication statusPublished - 2008 Oct 15

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Uterine Cervical Neoplasms
HeLa Cells
Survival
Cyclin D3
Cyclin E
Cell Cycle Proteins
Retinoblastoma
Peritoneum
Oncogene Proteins
Cyclin D1
Kaplan-Meier Estimate
G1 Phase
Colonic Neoplasms
Small Interfering RNA
Cell Cycle
Carcinogenesis
Up-Regulation
Survival Rate
Fibroblasts
Lymph Nodes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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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 G1-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 p21Waf1/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.",
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Eps8 decreases chemosensitivity and affects survival of cervical cancer patients. / Chen, Yun Ju; Shen, Meng-Ru; Chen, Yen Jen; Maa, Ming Chei; Leu, Tzeng-Horng.

In: Molecular Cancer Therapeutics, Vol. 7, No. 6, 15.10.2008, p. 1376-1385.

Research output: Contribution to journalArticle

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AU - Chen, Yun Ju

AU - Shen, Meng-Ru

AU - Chen, Yen Jen

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N2 - 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 G1-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 p21Waf1/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.

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