CSF2 Overexpression Is Associated with STAT5 Phosphorylation and Poor Prognosis in Patients with Urothelial Carcinoma

Background: Urothelial carcinoma (UC) commonly occurs in the urinary bladder (UB) and rarely in upper the upper urinary tract (UT). Its molecular pathogenesis, however, remains obscure. Though the constitutive phosphorylation of Signal Transducer and Activator of Transcription 5 (STAT5) is an important part of carcinogenesis generally, researchers have not systematically investigated this process specifically in relation to UC. The present study addresses this gap. Through data mining a published transcriptomic database of UBUCs (GSE32894), it identified Colony Stimulating Factor 2 (CSF2) as the stepwise upregulated gene of much significance among those related to the positive regulation of tyrosine phosphorylation of STAT5 (GO:0042523). Since the phosphorylation of STAT5, a key process in the development of UC, is closely associated with CSF2, we then examine CSF2 transcript and protein expression, justifying their association with clinicopathological features and survival in our well-established cohort of patients with UC. Design: Laser capture microdissection in conjunction with real-time qRT-PCR are used to detect CSF2 transcript levels in 24 UBUCs and 6 non-tumor urothelium samples. We then used the H-score method to evaluate the immunohistochemistry in order to determine CSF2 protein expression in 296 UBUCs and 340 UTUCs, respectively. After correlating protein expression status with key clinicopathological features, the prognostic significance of CSF2 protein expression was determined for disease-specific survival (DSS) and metastasis-free survival (MeFS). Results: We exclusively detected the CSF2 transcript, which was stepwise upregulated in tumor lesions (p=0.010). In both groups of UC we found overexpression of CSF2 significantly related to incremental pT status (UTUC, p=0.011; UBUC, p<0.001), as well as with perineural invasion (UTUC, p=0.002; UBUC, p=0.001). Univariate analysis found a close correlation between CSF2 overexpression and unfavorable prognosis for both DSS (UTUC, p=0.0001; UBUC, p<0.0001) and MeFS (UTUC, p=0.0001; UBUC, p=0.0002). High expression of CSF2 still remained prognostically for DSS (UTUC, p=0.015; UBUC, p=0.004) and MeFS (UTUC, p=0.008; UBUC, p=0.027) in multivariate comparison. Conclusion: Our data showed that overexpression of CSF2 was inferred in advanced disease status and poor clinical outcomes for both UTUC and UBUC patients, suggesting that CSF2 may serve as an important prognosticator and a potential therapeutic target of UC.