Prostate Cancer Risk: Role of Genetic Variation in the microRNA Stress Response to Arsenic Exposure

Wilder-Heimark 225X197

 Project Co-Leaders

NAU

Jason A. Wilder, Ph.D. Assoc. Professor, Dept. of Biological Sciences , College of Engineering, Forestry & Natural Sciences

UACC

Ronald L. Heimark, Ph.D. Professor, Dept. of Surgery, Vice Chair Surgical Research, College of Medicine

 

Abstract

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 in vitro.

 

Specific Aims

 

  1. Determine arsenic exposure perturbations in specific microRNAs that target key regulatory pathways in prostate carcinoma progression.
  2. Develop candidate human polymorphisms in selected microRNAs and their target genes as potential modifiers of arsenic exposure.
  3. Investigate the phenotypic consequences of candidate microRNA and target gene SNPs in arsenic induced models of cancer stem cell formation and malignancy.