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

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.

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

“…This traditional method has been widely published and delivers results that are predictive of those seen in xenograft studies [54,55]. Notably, in the present study, incubation with 5 lM of CPT alone provided significant inhibition of colony formation by both HCT116 and SW480 colorectal cell lines.…”

Hyper-dependence of breast cancer cell types on the nuclear transporter Importin β1

“…The results here suggest that the mechanistic basis is the reliance on elevated Impα/β1-dependent nuclear import efficiency by malignant cells; that Imp levels can contribute critically to tumour promotion has been shown for the oncoprotein c-myc and the transcription factor E2F1 [34,35]. The basis of the increased sensitivity of the tumour cells to Impβ1 knockdown at low siRNA concentrations is not clear, especially as the breast tumour cell types in this study replicate faster than nontransformed MCF10A cells, which can result in the dilution of siRNA, and have a higher abundance of Impβ1 transcript and protein in untreated cells, both of which can negatively impact RNAi efficiency [36,37].…”

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

“…Karyopherins are one group of carrier proteins involved in the selective nucleocytoplasmic transport. Accumulating evidences have identified the critical roles of karyopherins in malignant diseases and KPNA2 gains the most attention [21][22][23]. Previous report has measured the gene expression profiling of karyopherins in HCC and found overexpressed KPNA2 could promote the proliferation of HCC cells [7].…”