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PMID: 23907459 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

KPNA2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-Myc and downregulation of FOXO3a.

Cell death & disease ·Vol. 4 ·2013-08-01 ·Pages e745

Huang L, Wang HY, Li JD, Wang JH, Zhou Y, Luo RZ, Yun JP, Zhang Y, Jia WH, Zheng M

Abstract

Karyopherin alpha 2 (KPNA2), a member of the karyopherin family, has a central role in nucleocytoplasmic transport and is overexpressed in many cancers. Our previous study identified KPNA2 as significantly upregulated in epithelial ovarian carcinoma (EOC), correlating with poor survival of patients. However, the precise mechanism of this effect remains unclear. The aim of the present study was to examine the role of KPNA2 in the proliferation and tumorigenicity of EOC cells, and its clinical significance in tumor progression. Real-time quantitative RT-PCR analysis revealed high expression levels of KPNA2 in 162 out of 191 (84.8%) fresh EOC tissues, which was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, differentiation, histological type, recurrence, and prognosis of EOC patients. Our results showed that upregulation of KPNA2 expression significantly increased the proliferation and tumorigenicity of EOC cells (EFO-21 and SK-OV3) in vitro and in vivo, by promoting cell growth rate, foci formation, soft agar colony formation, and tumor formation in nude mice. By contrast, knockdown of KPNA2 effectively suppressed the proliferation and tumorigenicity of these EOC cells in vitro and in vivo. Our results also indicated that the molecular mechanisms of the effect of KPNA2 in EOC included promotion of G1/S cell cycle transition through upregulation of c-Myc, enhanced transcriptional activity of c-Myc, activation of Akt activity, suppression of FOXO3a activity, downregulation of cyclin-dependent kinase (CDK) inhibitor p21Cip1 and p27Kip1, and upregulation of CDK regulator cyclin D1. Our results show that KPNA2 has an important role in promoting proliferation and tumorigenicity of EOC, and may represent a novel prognostic biomarker and therapeutic target for this disease.

MeSH Terms
Animals Carcinoma, Ovarian Epithelial Cell Line, Tumor Cell Proliferation E2F1 Transcription Factor/metabolism Female Forkhead Box Protein O3 Forkhead Transcription Factors/genetics,metabolism G1 Phase Cell Cycle Checkpoints Humans Kaplan-Meier Estimate Mice Mice, Inbred BALB C Mice, Nude Middle Aged Multivariate Analysis Neoplasm Transplantation Neoplasms, Glandular and Epithelial/metabolism,mortality,pathology Ovarian Neoplasms/metabolism,mortality,pathology Prognosis Protein Transport Proto-Oncogene Proteins c-myc/genetics,metabolism Transcription, Genetic Tumor Burden Up-Regulation alpha Karyopherins/physiology
Chemicals
E2F1 Transcription Factor E2F1 protein, human FOXO3 protein, human Forkhead Box Protein O3 Forkhead Transcription Factors KPNA2 protein, human MYC protein, human Proto-Oncogene Proteins c-myc alpha Karyopherins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Huang L
State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
Wang H-Y
Li J-D
Wang J-H
Zhou Y
Luo R-Z
Yun J-P
Zhang Y
Jia W-H
Zheng M
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Article Info
Journal
Cell death & disease
Abbr.
Cell Death Dis
ISSN
2041-4889
DOI
10.1038/cddis.2013.256
Published
2013-08-01
Epub
2013-00-01
Pages
e745
Language
English
Region
England
NLM ID
101524092
PMCID
PMC3763430
Subset
IM
External Links
PubMed source DOI: 10.1038/cddis.2013.256 PMC Full Text View journal details
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