Exosomal microRNAs (miRNAs) are suggested to reflect molecular changes occurring in their cells of origin and are potential indicators in the early detection of cancers. This study aimed to determine whether certain exosomal miRNAs from tumor tissue can be used as noninvasive biomarkers for clear cell renal cell carcinoma (ccRCC). Based on ccRCC miRNA expression profiles and the literature, we selected six miRNAs (miR‐210, miR‐224, miR‐452, miR‐155, miR‐21, and miR‐34a) and analyzed their expression in tissues, sera, and serum exosomes through quantitative real‐time polymerase chain reaction in hypoxia‐induced (with CoCl2) renal cell lines. miR‐210, miR‐224, miR‐452, miR‐155, and miR‐21 were upregulated in tumor tissues compared with normal tissues. Serum miR‐210 and miR‐155 levels were higher in patients with ccRCC than in healthy controls (HCs). Furthermore, only exosomal miR‐210 was significantly upregulated in patients with ccRCC than in HCs. Moreover, receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve of 0.8779 (95% confidence interval, 0.7987‐0.9571) and a sensitivity and specificity of 82.5% and 80.0%, respectively. Moreover, exosomal miR‐210 was upregulated at an advanced stage, and Fuhrman grade and metastasis decreased significantly one month after surgery. Acute hypoxia exposure activates miR‐210 and release of exosomes with upregulated miR‐210 in both normal and tumor RCC cell lines and interferes with vacuole membrane protein 1 mRNA expression, especially in the metastatic ccRCC cell line. In conclusion, Serum exosomal miR‐210 originating from tumor tissue has potential as a novel noninvasive biomarker for the detection and prognosis of ccRCC.

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