Urinary miRNA 210-3P a specific non-invasive biomarker in clear cell renal cell carcinoma

INTRODUCTION AND OBJECTIVES: The identification of non- invasive biomarkers for the diagnosis and responsiveness to therapy of ccRCC may represent a relevant step-forward in ccRCC management. The aim of this study is to evaluate whether specific miRNAs deregulated in ccRCC tissues present altered levels also in urine specimens. METHODS: This study includes two independent cohorts of ccRCC patients who underwent surgery between March 2015 and May 2018. Urine specimens were collected at the time of surgery from all the patients, and for 71.7% of the patients, urine was collected also during follow-up. Fifty-four patients were male (69.2%) and 24 patients were female (30.7%) with a median age of 65.4 years old (range 36-84). All the cases presented a clear cell histotype of RCC at the histological examination. Urine samples were also collected from two groups of healthy donors of 34 and 36 individuals with characteristics comparable to the ccRCC patients included in the study. RESULTS: We evidenced that miR-21-5p, miR-210-3p and miR-221-3p resulted up-regulated in these ccRCC vs matched adjacent normal fresh frozen tissues, while miR-185-5p and miR-145- 5p did not show significant modulation. Our data evidenced that miR-210-3p resulted the most significantly up-regulated miRNA (p-value[0.0149). To investigate whether the miRNAs deregulated in ccRCC tissues may serve as useful clinical biomarkers, we selected miR-21-5p, miR-210-3p and miR-221-3p to evaluate their expression in 78 urine specimens. Urine were collected at time of surgery and during follow-up (with 15 months as median of time from surgery) from two independent cohorts of ccRCC patients; urine specimens from healthy donors were analyzed as well. Of note, miR-210-3p resulted significantly up-regulated in urine specimens collected from ccRCC patients at the time of surgery, compared to healthy donors’ samples, contrarily to miR-21-5p and miR-221-3p, which didn’t show increased levels in urine despite their trend of up-regulation observed in tumour tissues. Importantly, miR-210-3p levels resulted significantly reduced during follow-up in 56 ccRCC patients of the same cohort, for which follow-up urine samples were available. MiR-21-5p and miR-221-3p resulted unchanged also in the follow-up samples. CONCLUSIONS: This study not only supports the identification of miR-210-3p as non-invasive biomarker for ccRCC management but also highlights that only specific onco-miRNAs are accumulated in urine specimens of ccRCC patients. Of note, the urine level of miR- 210-3p resulted significantly reduced during follow-up samples highlighting this onco-miRNA as potential biomarker useful not only for diagnosis but also to assess complete resection or response to treatment of ccRCC patients.