Abstract
BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, and its prognosis in a metastatic stage is poor. Although therapeutic options are continuously improving, better combination therapies and individualized approaches are still needed. Reticulocalbin-1 (RCN1), located in the endoplasmic reticulum (ER), is associated with aggressiveness and poor prognosis in many solid tumors, but its role in ccRCC has not been analyzed before. METHODS: In this study, we performed in-silico transcriptomic data mining to analyze RCN1 expression at mRNA and protein levels using large publicly available databases and conducted the first large-scale cohort study on the impact of RCN1 in ccRCC, including data from 306 patients who underwent tumor resection at the Clinic of Urology, University Hospital Bonn. We examined the correlation of RCN1 expression with clinicopathological parameters and overall survival. Additionally, we analyzed the association of RCN1 expression with CD8 T-lymphocyte and macrophage infiltration. In vitro functional analysis was performed by silencing RCN1 using siRNA in Caki-1 and A498 cell lines to determine its role in tumor cell behavior. RESULTS: RCN1 is highly expressed in ccRCC at both the mRNA and protein levels in public databases, which was confirmed by our cohort data, where RCN1 was found to be highly and homogenously expressed in 63.7% of ccRCCs. High RCN1 expression was associated with shorter overall survival both at the mRNA (p < 0.001) and protein levels (p = 0.01). Furthermore, high RCN1 expression was correlated with higher tumor grade (p = 0.002), tumor stage (p = 0.036), presence of lymph node metastases (p = 0.004), and distant metastases (p = 0.017). Clusters of macrophages tended to correlate with RCN1 expression (p = 0.051), but no significant correlation was found between RCN1 expression and the amount of CD8 T-lymphocytes. Additionally, silencing RCN1 led to a significant reduction in tumor cell migration and invasion. CONCLUSION: Our results confirm that RCN1 is highly and homogenously expressed in ccRCC and correlates with poor prognosis and unfavorable clinicopathological parameters. RCN1 could serve as a reliable biomarker for prognosis in ccRCC and shows potential as a target for therapeutic approaches.