Prostate Cancer Risk: Role of Genetic Variation in the microRNA Stress Response to Arsenic Exposure
Jason A. Wilder, Ph.D. Assoc.
Professor, Dept. of Biological Sciences , College of Engineering, Forestry
& Natural Sciences
Ronald L. Heimark, Ph.D. Professor,
Dept. of Surgery, Vice Chair Surgical Research, College of Medicine
Arsenic exposure in drinking water has been found to be a carcinogen for the
urogenital system. Groundwater in many parts of the US exceeds EPA guidelines
for safe arsenic exposure. This is a particularly acute problem in Arizona
where several regions, including the Colorado Plateau and Verde Valley, have
high levels of arsenic in many groundwater sources. The origin of this arsenic
may include both past mining activities and naturally occurring deposits in
certain geological structures. For instance, on the Colorado Plateau the Supai
Sandstone formation is a layer that naturally contains very high concentrations
of arsenic. This formation underlies much of the lands of the Navajo Nation,
where ~30% of the population relies on untreated well water derived from deep
groundwater sources. A similar situation exists in the groundwater underlying
large portions of the Tohono O'odham Nation in southern Arizona. As such,
developing a detailed understanding of the mechanisms by which arsenic exerts
its carcinogenic influence is of particular relevance to Native American
communities in the Southwest. The long-term goal of this research project is to
determine if environmental arsenic exposure and genetic are linked to an
aggressive phenotype in prostate cancer in men. Prostate cancer is both
clinically and biologically a heterogeneous disease and can grow slowly with an
indolent natural history, or can progress aggressively and metastasize leading
to cancer death. The hypothesis to be tested is that an important mechanism of
arsenic toxicity is as a co-carcinogen to alter prostate carcinoma differentiation
through altering the normal regulatory mechanisms of specific non-coding
microRNAs. MicroRNAs regulate gene expression in response to cellular stress.
Thus, misexpression of candidate microRNAs in key pathways will be correlated
with mechanisms that underlie aggressive prostate cancer. From a human genomics
standpoint there are naturally occurring SNPs in genes encoding microRNAs that
could alter their effect by changing promoter regulation or the binding
sequence that interacts with target genes. In addition there are SNPs in the 3’UTR
of target genes that can have an important role in binding to the microRNA.
Recently, a SNP discovery project identified SNPs in microRNAs using a panel of
human DNAs representing global human diversity. Many SNP alleles discovered in
this work were found to be local in their distribution, suggesting the
possibility that population-specific variants could contribute to cancer risk.
This study did not include in its survey samples from any Native American
populations, meaning that we do not know of any alleles that may be uniquely
segregating in these groups. We will screen Native American cell line DNA for
novel SNPs affecting a microRNA network known to be involved in prostate cancer
progression. We will then test whether these variants affect cancer cell phenotype
- Determine arsenic
exposure perturbations in specific microRNAs that target key regulatory
pathways in prostate carcinoma progression.
- Develop candidate
human polymorphisms in selected microRNAs and their target genes as potential
modifiers of arsenic exposure.
- Investigate the
phenotypic consequences of candidate microRNA and target gene SNPs in arsenic
induced models of cancer stem cell formation and malignancy.