Login to Access Video or Poster Abstract: MP88-15
Sources of Funding: NONE

Introduction

The development of drug resistance in advanced bladder cancer remains a significant clinical challenge. Recently, there has been immense interest in the role that tumor exosomes play in cancer development, metastasis and drug resistance. Tumor cells have been shown to selectively package certain proteins and RNA material into exosomes for the purpose of cell to cell communication. After internalization, recipient cells show altered gene expression, which in turn, modifies their invasiveness, apoptotic rate and sensitivity to therapeutic drugs. Few studies have examined the role of exosomal microRNAs (miRNA) in transference of drug resistance in bladder cancer. We hypothesize, that specific miRNAs have distinct roles in the establishment of chemoresistance. Here we strive to identify exosomal miRNAs profiles and their roles in Cisplatin, Gemcitabine and Cisplatin/Gemcitabine chemoresistance in bladder cancer.

Methods

Three resistant sublines of the human CUB III bladder carcinoma cell line were developed by gradually exposing the cells to increasing doses of Gemcitabine, Cisplatin or a combination of Gemcitabine and Cisplatin, over a period of 6 months. Exosomes were harvested and characterized by nanoparticle tracking analysis. Exosomal miRNAs were profiled via qRT-PCR array analysis. These distinct exosomal miRNA signatures were investigated in several additional bladder carcinoma resistant cell lines.

Results

Chemoresistant CUB III cells exhibit distinct miRNA profiles within their exosomes, which is unique depending on the drug of treatment. Of the 759 miRNA profiled, sixteen were differentially expressed (at least two-fold) across all the CUBIII resistant sublines relative to their parental line. Our data showed that 10 miRs were consistently down-regulated and 6 miRNAs were up regulated. Among the differentially expressed exosomal miRNAs in the resistant sublines, miR-Let-7i-3p was the most significantly down-regulated while miR-21-5p was the highest up-regulated compared to their chemosensitive counterpart._x000D_

Conclusions

Our findings demonstrate that for each chemotherapeutic drug, resistant cells had differentially expressed miRNA profiles within their exosomes. Many of these miRNAs have been shown to play a role in oncogenesis or the development of drug resistance in other tumor types. After further validation these exosomal miRNAs may have utility as predictive biomarkers of treatment response and possibly as therapeutic targets to enhance drug response.

Funding

NONE