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.
Highlights
Nucleocytoplasmic transport occurs through large nuclear pore complexes in the nuclear membrane
Of the 26 863 genes detected by the Affymetrix GeneChip (Human Genome U133 Plus 2.0 Array) microarray, 19 genes were found to be upregulated in Epithelial ovarian carcinoma (EOC) cells, including Karyopherin alpha 2 (KPNA2), compared with human ovarian surface epithelial (HOSE) tissues
The pivotal finding of our study was the detection of KPNA2 upregulation in 84.8% (162/191) of primary EOC tumors that were significantly associated with poor prognosis in EOC patients
Summary
Nucleocytoplasmic transport occurs through large nuclear pore complexes in the nuclear membrane. Whereas some factors are able to diffuse passively through the pores, the transport of macromolecules larger than B40 kDa must be mediated by shuttle proteins, such as karyopherins.[1] A family of karyopherin a heterodimers mediated the classical nuclear import pathway, which recognize cargo proteins via their nuclear localization signals (NLSs). Karyopherin alpha 2 (KPNA2) is one of seven known karyopherin a proteins[2] that have central roles in nucleocytoplasmic transport. The KPNA2 protein ( known as importin a-1 or RAG cohort 1) is B58 kDa and comprises 529 amino acids. Its domain structure was defined between 1995 and 1996.3–6 The protein comprises an N-terminal hydrophilic importin b-binding domain; a central hydrophobic region consisting of 10 armadillo repeats, which binds to the NLS site of the cargo protein; and a short acidic C terminus, which has no reported function. Immunohistochemistry revealed that overexpression of KPNA2 in EOC was correlated with poor prognosis;[11] the precise mechanism underlying the correlation is unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
