Abstract
Molecular targeted therapy is a standard treatment for patients with advanced renal cell carcinoma (RCC). Sunitinib is one of the most common molecular-targeted drugs for metastatic RCC. Molecular mechanisms of sunitinib resistance in RCC cells is still ambiguous. The microRNA (miRNA) expression signature of patients with sunitinib failure in RCC was constructed using a polymerase chain reaction (PCR)-based array. Several miRNAs that were aberrantly expressed in RCC tissues from patients treated with sunitinib were identified in this analysis. MicroRNA-101 (miR- 101) was markedly suppressed in sunitinib treated RCC tissues. Restoration of miR-101 significantly inhibited cell migration and invasion in Caki-1 and 786-O cells. Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was directly suppressed by miR-101 in RCC cells, and overexpression of UHRF1 was confirmed in sunitinib-treated RCC tissues. The pathways of nucleotide excision repair and mismatch repair were significantly suppressed by knockdown of UHRF1. Our findings showed that antitumor miR-101- mediated UHRF1 pathways may be suppressed by sunitinib treatment.
Highlights
Renal cell carcinoma (RCC) accounts for over 80% of kidney cancers, and 338,000 new cases were diagnosed worldwide in 2012 [1]
We reviewed our miRNA expression data of 10 sunitinib-naïve renal cell carcinoma (RCC) specimens and 5 normal kidney tissues, and we constructed a signature of downregulated miRNAs in sunitinib-naïve RCC tissues (Supplementary Table S1)
We focused on miR-101, which showed the most dramatic downregulation in sunitinib-treated RCC, for further studies
Summary
Renal cell carcinoma (RCC) accounts for over 80% of kidney cancers, and 338,000 new cases were diagnosed worldwide in 2012 [1]. Sunitinib is one of the most common moleculartargeted drugs for metastatic RCC. A phase 3 clinical trial of sunitinib versus interferon alpha in patients with metastatic RCC ushered in the molecular-targeted era in the treatment of RCC [3]. Side effects, such as hand-foot syndrome, thrombocytopenia, general fatigue, and hypothyroidism, often occur with sunitinib treatment, sunitinib is still a standard treatment for metastatic RCC due to the relatively longer progression-free survival time and higher response rate [4,5,6]. Sunitinib therapy is often associated with treatment failure in patients with metastatic RCC
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