MicroRNA Profiling of Dogs with Transitional Cell Carcinoma of the Bladder Using Blood and Urine Samples – Beyond the Abstract

Transitional cell carcinoma (TCC) is prevalent in both canines and humans, and advanced TCC is associated with low survival rates (median survival time is ~6 months and ~12 months, respectively [1, 2]). For canine TCC patients the lack of a diagnostic test that is affordable, accurate, and practical, is a major factor which contributes to low survival rates. For human TCC patients with advanced disease, low survival rates are more likely due to lack of effective therapies/the ability to predict who will respond to a particular therapy, however, misdiagnosis can occur. The identification and development of improved diagnostic, prognostic, and/or predictive biomarkers could help improve TCC survival rates for both canines and human.

Multiple studies have demonstrated that miRNA can serve as excellent biomarkers; they are present and stable in body fluids, they often play a direct role in the disease process, and they are relatively easy and affordable to work with and assess [3]. In our recent article [4], we demonstrate that miRNA can be extracted from canine urine and that miR-103b and miR-16 expression levels can be used to distinguish between canine patients with TCC versus clinically normal patients as well as between TCC patients and patients with lower tract urinary disease (LUTD). The latter is important because TCC and LUTD patients often share many of the same signs and symptoms, and this can result in misdiagnosis and delayed treatment. It is noteworthy that in our study we observed statistically significant differences in miRNA expression only in urine samples, not blood samples. This finding, and the fact that alterations in miRNA expression which are observed in urine samples are more likely to reflect actual changes in miRNA expression which are occurring in bladder cells because they are shed into the urine [5, 6], supports the use of urine for TCC biomarker discovery studies.

To our knowledge, our study is the first to observe differential expression of miR-103b and miR-16 in urine samples from canine bladder cancer patients versus patients with LUTD. Decreased miR-103b expression has been observed in human patients with muscle-invasive bladder cancer (MIBC) and is associated with worse outcome [7], and dysregulation of miR-103b can result in altered expression of several molecules which play a role in carcinogenesis, for example, CCNE1, CDK2, CREB1, DICER, and PTEN [8] [9]. Decreased miR-103b expression has also been shown to promote increased proliferation and invasiveness in colorectal cancer cell lines [8, 10, 11]. A role for miR-16 in bladder carcinogenesis, or differential expression of miR-16 in TCC, has not previously been reported, however, decreased expression of miR-16 is associated with chronic lymphocytic lymphoma (CLL) and prostate cancer [12-14]. The combined data support further investigation of miR-103b and miR-16 as potential biomarkers for both canine and human TCC.

Another key finding from our study is that loss of coordinated expression of some of the urine-derived miRNAs assessed, including miR-34a, occurs in canine TCC patients. MiR-34a is well known to be regulated by p53 and dysregulation of the p53 signaling axis is a hallmark of advanced TCC [15, 16]. While further analyses are needed to validate this preliminary finding, our data indicate analysis of multiple miRNAs and their relative expression to each other within each patient sample may be a promising strategy for TCC biomarker discovery studies.   


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Written by:
Ruth L. Vinall1, Michael Kent2, and Paramita M. Ghosh3

1. Department Pharmaceutical & Biomedical Sciences, California Northstate University College of Pharmacy, Elk Grove, CA
2. Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA
3. Department of Urology, University of California Davis, Sacramento, CA

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