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Open Access Highly Accessed Research article

Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer

Hanbyoul Cho12, Joon-Yong Chung2, Kwon-Ho Song34, Kyung Hee Noh34, Bo Wook Kim2, Eun Joo Chung5, Kris Ylaya2, Jin Hee Kim34, Tae Woo Kim34, Stephen M Hewitt2* and Jae-Hoon Kim1*

Author Affiliations

1 Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, 146-92 Dogok-Dong, Gangnam-Gu, Seoul 135-720, South Korea

2 Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA

3 Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea

4 Department of Biochemistry, Korea University College of Medicine, Seoul, Korea

5 Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA

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BMC Cancer 2014, 14:545  doi:10.1186/1471-2407-14-545

Published: 28 July 2014

Abstract

Background

The apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer.

Methods

API5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues.

Results

API5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.

Conclusions

API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

Keywords:
API5; pERK1/2; Prognosis; Cervical cancer; Tissue microarray; Immunohistochemistry