Urothelial carcinomas are the most common malignancy of the urinary tract and are derived from the urothelium of the upper urinary tract (renal pelvis and ureter) or lower urinary tract (urinary bladder). Upper urinary tract urothelial carcinomas (UTUCs), in contrast with urinary bladder urothelial carcinomas, are relatively rare, accounting for 2% ~ 8% of urothelial carcinomas . A previous report disclosed that the ratio of incidences of urothelial carcinoma in the renal pelvis, ureter, and urinary bladder was approximately 3:1:51 . However, the prevalence of UTUC is higher in Taiwan, and the ratio was 1:2.08:6.72 in a single institution study in Taiwan that included 535 cases . Due to unknown reasons, the tumor stage of UTUC is high when discovered, which leads to an overall poor prognosis of patients with UTUC . Currently, various prognosticatory factors have been identified, including the tumor stage, lymph node status, growth pattern, tumor necrosis, and lymphovascular invasion. Many molecular markers, such as cadherin-1, hypoxia-inducible factor (HIF)-1α, and telomerase RNA, were also found to independently be associated with tumor recurrence and poor survival [5, 6].
Cyclin A is important in regulating cell cycles, including playing roles in initiating DNA replication in the S phase and preventing other cyclins from degrading. Expressions of cyclins are strictly regulated, and degradation of cyclin A in a timely manner is mandatory for the cell cycle to enter metaphase . Overexpression of cyclin A and dysregulation of CDK-cyclin complexes promote tumor cell growth . Cyclin A is also associated with high proliferative activity in various carcinomas, including breast cancer, lung cancer, sarcomas, and hematological malignancies . Furihata et al. demonstrated that overexpression of cyclin A in UTUC is associated with poor cancer-specific survival, the tumor grade, and the tumor growth pattern .
HuR, a member of the embryonic lethal abnormal vision (ELAV) protein family, is a turnover- and translation-regulatory RNA-binding protein (TTR-RBP) that regulates the translation and stability of cytoplasmic messenger (m)RNA . HuR was found to be upregulated in almost all malignancies tested, including carcinomas originating in the breast, colon, stomach, pancreas, esophagus, prostate, lung, thyroid, etc . It binds directly to the U- and AU-rich elements in the 3’-untranslated region (UTR) of most target mRNAs, which are termed AREs, or the 5’UTR of some target mRNAs. HuR is predominantly localized in nuclei, but translocation to the cytoplasm is necessary for its regulation upon the expression of target mRNAs. HuR can stabilize many target mRNAs, including those encoding proteins that take part in tumorigenesis or carcinogenesis . Furthermore, translation of several target mRNAs, including cyclin A2, can be upregulated by HuR, although the exact mechanism is still unclear.
Many studies showed that HuR is a prognostic factor in various carcinomas, such as colorectal adenocarcinoma, breast carcinoma, ovarian carcinoma, etc [14–16]. HuR stabilizes the mRNA of cyclin A2 and increases its translation. Previous studies showed that it plays a critical role in increasing the proliferative activity of colorectal carcinoma, gastric adenocarcinoma, and oral cancer [17–19]. However, correlations of HuR with biologically and clinicopathologically significant factors of UTUC are unknown.
In this study, by applying an immunohistochemical study to our well-characterized case collection, we evaluated the association of HuR overexpression with clinicopathological parameters and survival of UTUC patients.