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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
DNMT1: an emerging target in the treatment of invasive urinary bladder cancer
Deepika Dhawan1, José A Ramos-Vara, Noah M Hahn
1Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907, USA; Purdue Oncological Sciences Center, Purdue University, West Lafayette, IN 47907, USA.
Objectives:
More than 14,000 people die from invasive urothelial carcinoma (iUC) of the urinary bladder each year in the USA, and more effective therapies are needed. Naturally occurring canine iUC very closely resembles the disease in humans and serves as a highly relevant translational model for novel therapy of human iUC. Work was undertaken to identify new targets for anticancer therapy in dogs with the goal of translating successful therapeutic strategies into humans with iUC.
Materials And Methods:
Microarray expression analyses were conducted on mRNA extracted from canine normal bladder (n = 4) and iUC tissues (n = 4) using Genome Array 1.0 and analyzed by GeneSpring GX 11, with the stringency of P < 0.02 and a ≥ 2-fold change. The genes thus identified were further analyzed for functional and pathway analysis using Protein ANalysis THrough Evolutionary Relationships (PANTHER) Classification System. In selecting genes for further study, consideration was given for evidence of a role of the gene in human iUC. From these analyses, DNA methyltransferase 1 (DNMT1) was selected for further study. Immunohistochemistry (IHC) of canine normal bladder and iUC tissues was performed to confirm the microarray expression analyses. The effects of targeting DNMT1 in vitro was assessed through MTT assay and Western blot of canine iUC cells treated with 5-azacitidine (5-azaC) and trichostatin A (TSA).
Results:
DNMT1 was expressed in 0 of 6 normal canine bladder samples and in 10 of 22 (45%) canine iUC samples. The proliferation of canine iUC cells was inhibited by 5-azaC (at concentrations ≥ 5 μm) and by TSA (at concentrations ≥ 0.1 μm). Western blot results were supportive of DNMT1-related effects having a role in the antiproliferative activity.
Conclusions:
Microarray expression analyses on canine tissues identified DNMT1 as a potentially "targetable" gene. Expression of DNMT1 in canine iUC was confirmed by IHC, and in vitro studies confirmed that drugs that inhibit DNMT1 have antiproliferative effects. These findings are similar to those recently reported in human iUC and are also in line with results of a preclinical (prehuman) trial of 5-azaC in dogs with naturally occurring iUC. DNMT1 has excellent potential as a target for iUC therapy in humans.
Insights
Canine invasive urothelial carcinoma (iUC) models reveal DNA methyltransferase 1 (DNMT1) as a promising therapeutic target. Inhibiting DNMT1 showed significant antiproliferative effects in canine iUC cells, supporting its potential for human iUC treatment.
Area of Science:
- Comparative oncology
- Translational research
- Cancer genomics
Background:
- Invasive urothelial carcinoma (iUC) of the urinary bladder causes significant mortality in the USA.
- Naturally occurring canine iUC closely mimics human disease, offering a valuable translational model.
- There is a critical need for novel therapeutic strategies for iUC.
Purpose of the Study:
- To identify novel therapeutic targets for canine iUC.
- To evaluate the translational potential of canine iUC research for human iUC therapy.
- To investigate DNA methyltransferase 1 (DNMT1) as a potential iUC target.
Main Methods:
- Microarray expression analysis of normal and iUC canine bladder tissues.
- Functional and pathway analysis of identified genes using PANTHER.
- Immunohistochemistry (IHC) to confirm DNMT1 expression.
- In vitro assessment of DNMT1 inhibition using 5-azacitidine (5-azaC) and trichostatin A (TSA) on canine iUC cells.
Main Results:
- DNMT1 was significantly expressed in canine iUC tissues but not in normal bladder tissues.
- 5-azaC and TSA demonstrated significant antiproliferative effects on canine iUC cells in vitro.
- Western blot analysis supported the role of DNMT1 in the observed antiproliferative activity.
Conclusions:
- Microarray analysis identified DNMT1 as a targetable gene in canine iUC.
- DNMT1 expression in canine iUC was confirmed by IHC.
- In vitro studies validated the antiproliferative effects of DNMT1 inhibitors, aligning with human iUC research and preclinical trials.
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