Abstract 2526: MicroRNA expression signature of patients with tyrosine kinase inhibitors failure: miR-10a-5p inhibits cancer cell aggressiveness in renal cell carcinoma

Abstract

Abstract Renal cell carcinoma (RCC) is a disease in which cells undergo oncogenic transformation in the kidney tubules. The five-year survival rate of advanced stage RCC is poor (5-10%) due to recurrence or distant metastasis. Recently, anti-angiogenic multi-tyrosine kinase inhibitors (TKIs) have been developed and have been used as first and second line treatments for RCC. However, these treatments extend progression-free survival only slightly, and relapse and metastasis eventually develop in most patients. The molecular mechanisms of RCC recurrence, metastasis and drug resistance are not yet fully understood. Therefore, analysis of the molecular mechanisms underlying RCC development and progression and studies of novel oncogenic pathways based on current genome-based approaches could significantly improve diagnosis, therapy, and prevention of the disease. miRNAs (miRNAs) are small noncoding RNAs that function to fine tune the expression of protein coding/noncoding RNAs by repressing translation or cleaving RNA transcripts in a sequence-depending manner. The unique characteristic function of miRNAs is to regulate RNA transcripts in human cells. Therefore, dysregulated expression of miRNAs can disrupt tightly regulated RNA networks in cancer cells. In this study, we constructed a miRNA expression signature to identify pathways activated by TKI treatment using autopsy specimens from patients with RCC. We have sequentially identified tumor-suppressive miRNA and its regulated RCC pathways based on the signature. The aim of this study was to investigate the functional significance of miR-10a-5p and to identify the molecular targets and pathways mediated by miR-10a-5p in RCC cells. The expression levels of miR-10a-5p were significantly reduced in RCC clinical specimens and RCC cell lines compared with non-cancerous kidney tissues (P < 0.001). TCGA data showed that the overall survival of low miR-10a-5p expression group was significantly shorter than that of high expression group (P = 0.00408). Restoration of miR-10a-5p significantly inhibited cancer cell migration and invasion in RCC cell lines (P < 0.0001). Spindle and kinetochore associated complex subunit 1 (SKA1) was identified as a direct target gene of miR-10a-5p by genome-wide gene expression analysis and in silico analysis. Overexpression of SKA1 was observed in RCC clinical specimens. Moreover, the overall survival of high SKA1 expression group was significantly shorter than that of low expression group by TCGA analysis (P = 1.44E-07). Tumor-suppressive miR-10a-5p was identified by using miRNA signature of patients with TKI failure. Overexpression of SKA1 might be involved in RCC aggressiveness, metastasis and drug resistance. Elucidation of tumor-suppressive miRNAs regulated molecular pathways and targets could provide new information on potential therapeutic strategies in the disease. Citation Format: Takayuki Arai, Atsushi Okato, Akira Kurozumi, Mayuko Kato, Yusuke Goto, Keiichi Koshizuka, Satoko Kojima, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki. MicroRNA expression signature of patients with tyrosine kinase inhibitors failure: miR-10a-5p inhibits cancer cell aggressiveness in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2526. doi:10.1158/1538-7445.AM2017-2526