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Open Access Research article

HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma

Peir-In Liang1, Wei-Ming Li2, Yu-Hui Wang3, Ting-Feng Wu4, Wen-Ren Wu5, Alex C Liao6, Kun-Hung Shen6, Yu-Ching Wei7, Chung-Hsi Hsing8, Yow-Ling Shiue5, Hsuan-Ying Huang7, Han-Ping Hsu9, Li-Tzon Chen101112, Ching-Yih Lin1314, Chein Tai4, Chun-Mao Lin15* and Chien-Feng Li11045*

Author Affiliations

1 Department of Pathology, Chi-Mei Foundational Medical Center, Tainan, Taiwan

2 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

3 Institute of Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan

4 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

5 Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan

6 Department of Urology, Chi-Mei Foundation Medical Center, Tainan, Taiwan

7 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

8 Department of Anesthesiology, Chi-Mei Foundation Medical Center, Tainan, Taiwan

9 College of Medicine, China Medical University, Taichung, Taiwan

10 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

11 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

12 Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan

13 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Foundation Medical Center, Tainan, Taiwan

14 Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan

15 College of Medicine, Taipei Medical University, Taipei, Taiwan

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BMC Cancer 2012, 12:611  doi:10.1186/1471-2407-12-611

Published: 21 December 2012

Abstract

Background

HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs).

Methods

In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors.

Results

HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015).

Conclusions

HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy.

Keywords:
Upper urinary tract urothelial carcinoma; HuR; Cyclin A; Prognosis