230 Toll-like receptor 4-dependent, urine-induced activation of the stress sensor inositol-requiring protein 1 (IRE1) pathway in bladder cancer

Abstract

INTRODUCTION AND OBJECTIVES: Generally in microRNA (miRNA) biogenesis, one strand (guide strand) of the duplex may potentially act as a functional miRNA and incorporated into the RNA-induced silencing complex and regulating target genes. In contrast, other strand (passenger strand: miRNA*) is disintegrated quickly. Our miRNA expression signature of bladder cancer (BC) by using deep-sequencing revealed that tumor-suppressive miRNA-145 and its passenger strand of miRNA-145* were significantly reduced in cancer tissues, suggesting these function as tumor suppressors in BC cells. The aim of the study was to investigate functional significance of miRNA-145* and its regulated molecular targets/ pathways in BC. METHODS: We evaluated the expression levels of miR-145/ miR-145* in 43 BC clinical specimens and 12 normal bladder epithelia by real-time PCR. The functional analysis of the miRNA and molecular targets/pathways searching strategies were described as our previous studies (J Urol,192:1822-1830,2014; FEBS Lett,588:3170-3179,2014; PLoS One,9:e84311,2014). RESULTS: Expression levels of miR-145 and miR-145* were significantly lower than that in normal bladder epithelia (P < 0.0001). Gain-of-function studies revealed that cell proliferation, migration, and invasion were significantly inhibited in both miR-145 and miRNA-145* transfection into BC cell lines (each, P < 0.001). Combination of gene expression analysis of miR-145*-transfectants and in silico analysis showed that several oncogenic genes (HK2, YES1, FOSL1 etc.) were identified as miR-145* regulation in BC cells. CONCLUSIONS: Our genome-wide miRNA expression signature showed that miR-145* as a tumor-suppressive miR-145 passenger strand frequently reduced in BC cells and acts as a tumorsuppressor. Elucidation of miR-145/145*-mediated novel cancer pathways provide new insights of the potential mechanisms of BC oncogenesis. Furthermore, tumor-suppressive miR-145/145* might be contributed to development of miRNA-based cancer therapeutics in the disease.