High expression of KPNA2 defines poor prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy

Abstract

BackgroundTo analyze the expression of karyopherin alpha 2 (KPNA2) in upper tract urothelial carcinoma (UTUC) and to investigate whether the KPNA2 expression provides additional prognostic information following radical nephroureterectomy (RNU).MethodsA tissue microarray (TMA) containing samples from 176 patients with UTUC who underwent RNU at our institute was analyzed for KPNA2 expression using immunohistochemistry. KPNA2 expression in normal urothelial cell line and urothelial carcinoma cell lines was evaluated by western blot analysis. Using RNA interference in vitro, the effects of KPNA2 inhibition on cellular viability, migration and apoptosis were determined.ResultsKPNA2 expression was significantly upregulated in the UTUC samples compared with the adjacent normal urothelial tissues. High KPNA2 immunoreactivity was identified as a predictor of bladder recurrence (hazard ratio [HR]: 2.017, 95% CI 1.13-3.61, p = 0.018), poor disease-free survival (DFS, HR: 2.754, 95% CI 1.68-4.51, p = 0.001) and poor overall survival (OS, HR: 4.480, 95% CI 1.84-10.89, p = 0.001) for patients with UTUC after RNU. Furthermore, high KPNA2 immunoreactivity was independent of the conventional predictive factors in a multivariate analysis. Additional in vitro experiments revealed that KPNA2 expression was higher in urothelial carcinoma cell lines than in normal urothelial cell line. KPNA2 inhibition with a specific siRNA decreased cell viability and migration and increased apoptosis in urothelial carcinoma cell lines.ConclusionsKPNA2 is a novel independent prognostic marker for bladder recurrence, DFS and OS of UTUC patients who have undergone RNU. Moreover, these data suggest that KPNA2 may be a promising therapeutic target for UTUC.

Analysis of Microarray Data on Gene Expression and Methylation to Identify Long Non-coding RNAs in Non-small Cell Lung Cancer

“…KPNA2 may play critical roles in carcinogenesis, cell differentiation, transcription regulation and immune response. Recently studies have demonstracted that high expression of KPNA2 is associated with poor prognosis of esophageal squamous cell carcinoma12, epithelial ovarian carcinamos13, gastric cancer14, prostate cancer15, upper tract urothelial carcinoma16 and breast cancer17. Teng et al .…”

KPNA2 promotes cellular proliferation and inhibits apoptosis in the Saos-2 osteosarcoma cell line

“…How KPNA2 contributes to tumorigenesis and the development of osteosarcoma is still unclear. Yoichi Miyamoto reported that functional importin α1 (KPNA2) is located at the cell surface and may accelerate the proliferation of cancer cells by affecting FGF1 signaling in cancer cells (24). Other studies also reported that microRNAs may regulate KPNA2 expression in cancers [25].…”

Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

“…The value of nuclear transporters such as KPNB1, XPO1 and CSE1L as prognostic tools is still under investigation and data supporting this are only available for a select few cancers. In contrast, KPNA2 has been well established as a prognostic marker in various cancers including: breast cancer, brain cancer, gastric cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, melanoma, lung cancer and oesophageal cancer . Dahl et al's research in breast cancer was the first to identify KPNA2 as a prognostic marker .…”