Login to Access Video or Poster Abstract: MP39-08
Sources of Funding: none

Introduction

Recently, tyrosine kinase inhibitors (TKIs) treatment is a standard treatment for patients with advanced renal cell carcinoma (RCC). During sequencing TKI-based therapies, RCC cells acquire the resistance to TKI-treatment. To date, no effective therapeutic resumes for patients with TKI-treatment failure, and overall survival of these patients is extremely poor. _x000D_ A unique characteristic of microRNA (miRNA) is that a single miRNA regulates a large number of RNA transcripts in human cells. Thus, dysregulated miRNA expression disrupts tightly regulated RNA networks in cancer cells. Currently, numerous studies have indicated that dysregulated miRNAs involved in cancer cell development, metastasis and drug resistance. Identification of aberrantly expressed miRNAs is the first step to defining the oncogenic and drug resistance RNA networks in RCC cells._x000D_ Our miRNA signature of RCC revealed that miR-149-5p was significantly reduced in RCC specimens. In this study, we focused on the functional significance of miR-149-5p in RCC cells by identifying the pathologic targets of miR-149-5p and the RNA networks that contribute to RCC aggressiveness and drug resistance._x000D_

Methods

TCGA database was applied to investigate the clinical outcome of the patients. Gain-of-function studies were performed using transfection of mature miR-149-5p into RCC cell lines. Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-149-5p in RCC cells.

Results

The expression levels of miR-149-5p were significantly reduced in RCC clinical specimens (P < 0.001). Ectopic expression of miR-149-5p were significantly suppressed cancer cell proliferation. Gene expression and in silico analysis identified that Forkhead box protein M1 (FOXM1) was a target of miR-149-5p regulation. Knockdown study using si-FOXM1 showed that expression of FOXM1 enhanced RCC cell aggressiveness. A large number of cohort analysis based on TCGA data (n = 261) indicated that the overall survival of high FOXM1 expression group was significantly shorter than that of low expression of FOXM1 group (p < 3.35E-06).

Conclusions

Our present data indicated that miR-149-5p act as a tumor-suppressor targeting FOXM1 in RCC cells and this axis deeply involved RCC pathogenesis. Elucidation of tumor-suppressive miRNA-regulated molecular pathways and targets could provide new information on potential therapeutic strategies in the disease.

Funding

none