Objective: Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of RCC and comprises approximately 70% of all RCC cases, with high incidence and metastatic relapse. Sunitinib is a first-line drug for treating patients with metastatic RCC but drug resistance inevitably occurs in a vast majority of patients after 15 months of systematic treatment. Herein, we attempted to explain the possible mechanism of sunitinib resistance in ccRCC.
Methods: Two expression profiles with accession numbers GSE64052 and GSE76068 in the GEO were utilized to identify differentially expressed genes (|log2FC| ≥ 1 with adjusted P < .05) between sunitinib sensitivity and sunitinib resistance in ccRCC. The study included tumor and matched non-tumor kidney tissues obtained from 64 ccRCC patients who underwent nephrectomy before adjuvant therapy.
Results: The gene expression profiles of GSE64052 and GSE76068 datasets yielded 92 and 66 differentially expressed genes between sunitinib sensitivity and sunitinib resistance in ccRCC, respectively. The PPI analysis revealed CTGF, RSAD2, and THBS1 as hub genes among which only THBS1 was found to be correlated with the survival of ccRCC patients. miR-96-5p and miR-29b-3p were common miRNAs targeting THBS1 and correlated with the survival of ccRCC patients. The luciferase activity assays demonstrated THBS1 as the target gene of miR-96-5p and miR-29b-3p. Results of qRT-PCR provided evidence of higher expressions of miR-96-5p and miR-29b-3p with a lower expression of THBS1 in tumor kidney tissues than matched non-tumor kidney tissues and in tumor kidney tissues of responders than those of non-responders. More specifically, elevated expressions of miR-96-5p, miR-29b-3p, and a declined expression of THBS1 were observed in tumor samples with advanced ccRCCs and higher Fuhrman grades. Pearson correlation analysis yielded significantly negative correlations between miR-96-5p and THBS1 (P < .006, r = -0.339), between miR-29b-3p and THBS1 (P < .05, r = -0.421).
Conclusion: Our study suggests that miR-96-5p- and miR-29b-3p-mediated THBS1 inhibition is associated with sunitinib resistance in ccRCC, offering a better understanding of the mechanism elucidating acquired drug resistance in ccRCC.