Necdin Overexpression Predicts Poor Prognosis in Patients with Urothelial Carcinomas of the Upper Urinary Tract and Urinary Bladder

I-Wei Chang; Yu-Hui Wang; Wen-Jeng Wu; Peir-In Liang; Wei-Ming Li; Bi-Wen Yeh; Ting-Feng Wu; Hong-Lin He; Steven Kuan-Hua Huang; Chien-Feng Li

doi:10.7150/jca.13638

Necdin Overexpression Predicts Poor Prognosis in Patients with Urothelial Carcinomas of the Upper Urinary Tract and Urinary Bladder

J Cancer. 2016 Jan 10;7(3):304-13. doi: 10.7150/jca.13638. eCollection 2016.

Authors

Affiliations

¹ 1. Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan;; 2. School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan;
² 3. Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan;; 4. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan;
³ 5. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;; 6. Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;; 7. Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;; 8. Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan;; 9. Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan;.
⁴ 10. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;
⁵ 11. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan;
⁶ 1. Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan;
⁷ 12. Department of Urology, Chi Mei Medical Center;
⁸ 4. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan;; 11. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan;; 13. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;; 14. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Abstract

Background and aims: Oncogenesis is a multistep process, resulting from the accumulations of multiple mutations. Of these mutations, self-sufficiency in growth signals, i.e., disruption of cell growth regulation, is the first episode. Nonetheless, the genes associated with cell growth dysregulation have seldom been systematically evaluated in either urothelial carcinomas of upper urinary tract (UTUC) or urothelial carcinomas of urinary baldder (UBUC). By data mining a published transcriptomic dataset of UBUCs (GSE31684), we identified the NDN gene as one of the most significant of those associated with the regulation of cell growth and found this gene is associated with advanced tumor status and metastatic disease (GO:0001558). Accordingly, we analyzed NDN transcript and protein expression with their clinicopathological significance.

Materials and methods: We used real time RT-PCR to detect NDN transcript levels in 27 UTUCs and 27 UBUCs, respectively. Immunohistochemical study was performed to determine NDN protein (a.k.a. Necdin) expression evaluated by H-score method in 340 UTUCs and 295 UBUCs. NDN expression was further correlated with clinicopathological features and disease-specific survival (DSS) and metastasis-free survival (MeFS).

Results: NDN transcriptional level was significantly higher in UCs of both sites with stepwise more advanced pT statuses. Through immunohistochemistry, we found NDN protein expression was significantly associated with adverse clinicopathological parameters, e.g., advanced pT status, nodal metastasis, high grade histological patterns, and frequent mitotses (all P<0.05). In univariate analysis, NDN overexpression not only predicted worse DSS and MeFS in both the UTUC and UBUC groups, it also served as an independent prognostic factor for DSS and MeFS in multivariate analysis (all P<0.05).

Conclusions: NDN may play an important role in tumor progression in UC and could serve as a prognostic biomarker and a potential novel therapeutic target in UC.

Keywords: NDN gene; Necdin; Prognosis.; Urothelial carcinoma.