Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2,3,7,8- tetrachlorodibenzo--dioxin (TCDD) have been closely correlated to MM by epidemiologic studies, yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor, guardian of the human genome. Genomic instability (chromosome translocation, aneuploidy, and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs, microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first, we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis, reporter expression, and immunoblotting analyses;second, we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays;third, we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA, that is upregulated by dioxin, will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis.

Public Health Relevance

TP53 gene alterations are rare and late events in multiple myeloma (MM), the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs), a class of newly discovered small noncoding RNAs, to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations, and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138688-04
Application #
8315740
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Johnson, Ronald L
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$396,576
Indirect Cost
$102,536
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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