KPNA2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-Myc and downregulation of FOXO3a.
KPNA2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-Myc and downregulation of FOXO3a.
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KPNA2 通过上调 c-Myc 和下调 FOXO3a 促进上皮性卵巢癌的细胞增殖和致瘤性
DOI：
10.1038/cddis.2013.256
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发表时间：
2013-08-01
影响因子：
9
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核浆转运蛋白α 2（KPNA 2）是核浆转运蛋白家族的成员，在核浆转运中起核心作用，并在许多癌症中过表达。我们先前的研究发现KPNA 2在上皮性卵巢癌（EOC）中显著上调，与患者的生存率低相关。然而，这种效应的确切机制仍不清楚。本研究的目的是研究KPNA 2在EOC细胞增殖和致瘤性中的作用及其在肿瘤进展中的临床意义。实时荧光定量RT-PCR检测结果显示，KPNA 2在191例卵巢上皮性癌组织中有162例（84.8%）高表达，其表达与国际妇产科联盟（FIGO）的临床分期、分化程度、组织学类型、复发及预后密切相关。我们的研究结果表明，上调KPNA 2的表达显着增加EOC细胞（EFO-21和SK-OV 3）在体外和体内的增殖和致瘤性，通过促进细胞生长速率，病灶形成，软琼脂集落形成，裸鼠肿瘤形成。与此相反，敲低KPNA 2在体外和体内有效地抑制这些EOC细胞的增殖和致瘤性。KPNA 2对卵巢癌的作用机制可能是通过上调c-Myc基因表达，增强c-Myc基因转录活性，激活Akt活性，抑制FOXO 3a活性，下调细胞周期蛋白依赖性激酶（cyclin-dependent kinase，CDK）抑制剂p21 Cip 1和p27 Kip 1的表达，上调CDK调节剂cyclinD 1的表达，从而促进G1/S细胞周期转换。我们的研究结果表明，KPNA 2在促进上皮性卵巢癌的增殖和致瘤性中具有重要作用，并可能代表这种疾病的新的预后生物标志物和治疗靶点。
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.