miRNAs are small 20-22 nucleotide long RNA molecules that regulate important cellular processes by suppressing expression of multiple mRNAs. By analyzing two tumor cell types, one of which exhibits an epithelial gene-expression profile (Type II) and one a mesenchymal gene-expression profile (Type I), and which differ in their responses to the apoptosis inducing activity of Fas ligand and Taxanes, we identified the miRNA let-7 as a marker for more differentiated and less aggressive Type II cancer cells. The early embryonic gene HMGA2 was found to be a prime target of let-7 and was found to be upregulated in tumor cells from advanced ovarian cancer patients. A bioinformatics analysis identified a set of let-7 regulated oncofetal genes (LOGs) that may be upregulated in many human cancers giving cancer cells the migratory and invasive properties and the drug resistance of embryonic cells. Another screen specifically designed to identify miRNAs expressed only in epithelial cells identified the miR-200 family. MiR-200 family members suppress ZEB1 and ZEB2, two transcription factors known to be powerful EMT inducers through suppression of the expression of E-cadherin. I hypothesize that let-7 and miR-200 contribute to two different key stages of cancer progression: 1) Let-7 suppresses the expression of a number of oncofetal genes preventing dedifferentiation of cancer and early cancer progression and 2) miR-200 maintains an epithelial phenotype, thereby preventing metastases, by targeting factors that induce epithelial/mesenchymal transition (EMT). Loss of let-7, therefore, allows early cancer progression, whereas miR-200 is expected to drive EMT in cancer cells resulting in more invasive cancers. To study the role of miRNAs in tumor progression I propose the following four specific aims:
Aim 1. Monitor and compare the expression of let-7 and miR-200 during cancer progression.
Aim 2. Determine the function of let-7 and miR-200 in cancer growth and progression in vivo.
Aim 3. Determine how let-7 and miR- 200 affect cancer cells.
Aim 4. Identify let-7 regulated genes that confer resistance of advanced cancers to chemotherapy. Ultimately this proposal should result in a better understanding of the process of tumor progression and the contribution of miRNAs. The results could pave the way to better diagnostic tools (detection of LOGs in human cancers) and to improved cancer therapy (reintroducing let-7 and miR-200) into tumor cells.

Public Health Relevance

Micro (mi)RNAs are small RNA molecules that target various messenger RNAs in cells so that they cannot be translated into proteins and it has become clear that miRNAs are key players in regulating differentiation processes and cancer. This proposal is aimed at defining the function of the two miRNA families, let-7 and miR-200 and their targets in cancer progression. The results of this study have the potential to improve cancer diagnostics and treatment through detection of miRNA targets and modulating the expression of miRNAs and/or their targets in human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149356-12
Application #
8267742
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Jhappan, Chamelli
Project Start
2000-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
12
Fiscal Year
2012
Total Cost
$272,177
Indirect Cost
$82,139
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Ceppi, Paolo; Hadji, Abbas; Kohlhapp, Frederick J et al. (2014) CD95 and CD95L promote and protect cancer stem cells. Nat Commun 5:5238
Boyerinas, Benjamin; Park, Sun-Mi; Murmann, Andrea E et al. (2012) Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1. Int J Cancer 130:1787-97
Schickel, Robert; Park, Sun-Mi; Murmann, Andrea E et al. (2010) miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell 38:908-15