title: HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma.
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.
authors.affiliation: Department of Pathology, Chi-Mei Foundational Medical Center, Tainan, Taiwan.
authors.forename: Peir-In
authors.initials: PI
authors.lastname: Liang
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Li
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Wang
authors.forename: Ting-Feng
authors.initials: TF
authors.lastname: Wu
authors.forename: Wen-Ren
authors.initials: WR
authors.lastname: Wu
authors.forename: Alex C
authors.initials: AC
authors.lastname: Liao
authors.forename: Kun-Hung
authors.initials: KH
authors.lastname: Shen
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Wei
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Hsing
authors.forename: Yow-Ling
authors.initials: YL
authors.lastname: Shiue
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.forename: Han-Ping
authors.initials: HP
authors.lastname: Hsu
authors.forename: Li-Tzon
authors.initials: LT
authors.lastname: Chen
authors.forename: Ching-Yih
authors.initials: CY
authors.lastname: Lin
authors.forename: Chein
authors.initials: C
authors.lastname: Tai
authors.forename: Chun-Mao
authors.initials: CM
authors.lastname: Lin
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D019925:Cyclin A / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D018572:Disease-Free Survival; D051959:ELAV Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D014571:Urologic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
chemical_list: D019925:Cyclin A; D051959:ELAV Proteins