Colorectal cancer (CRC) has served as a unique platform for durable insights into and advances in molecular pathogenesis, chemoprevention, diagnosis, and therapy, not only in this venue but expanded into other disease states. The elucidation of these comprehensive aspects of CRC has been facilitated through the identification of key genes and molecular pathways. It is well accepted that the majority of sporadic colorectal cancers feature the chromosomal instability pathway, involving alterations in key tumor suppressor genes (APC and p53, but also SMAD4) and oncogenes (especially Ras, but also EGFR, c-myc, B-Raf) and their downstream effectors. A subset of sporadic colon cancers undergo microsatellite instability (MSI) pathway, typically right-sided with B-Raf mutations but without Ras mutations. Recently, it has been advocated that certain colorectal cancers feature hypermethylation. We have genetically and physically mapped a region of loss of heterozygosity (LOH) on chromosome 22q13.31 as a basis to understand the role of new genes in colorectal carcinogenesis (and other cancers). We now have discovered a new telomeric region of LOH, which harbors two microRNAs, namely Let-7a3 and Let-7b, and these microRNAs are downregulated in up to 40% of colorectal cancers. MicroRNAs have become increasingly recognized for their pivotal, diverse roles in development, differentiation, proliferation, and cancer, which is achieved the degradation or interference with translation with messenger RNAs. We hypothesize that the Let-7a3 and Let-7b microRNAs are instrumental in colorectal cancer progression, and this may be achieved by targeting the Ras oncogene, and also, the c-myc oncogene. This novel hypothesis will be pursued by the following interrelated Specific Aims: (1). To identify the roles of the Let-7a3 and Let-7b microRNAs in colorectal cancer. A. To determine the relationship between these microRNAs and clinical parameters and molecular parameters;B. To determine the function(s) of Let7a and Let7b in colorectal carcinogenesis through genetic /overexpression/knockdown studies of these microRNAs with determination of effects upon cellular proliferation, apoptosis, migration and invasion, which are critical features of the colon cancer initiation and progression. (2). To determine if the Ras and c-myc oncogenes represent targets of Let-7a3 and Let- 7b. This will be achieved through examination of Ras transcriptional and protein activities in the setting of genetic approaches, namely Let-7a3 and Let-7b overexpression/knockdown. (3) To determine the functional consequences of restoration and inhibition of Let-7a3 and Let-7b in colon cancer cells in vivo. This will be assessed by innovative three-dimensional organotypic cultures, which mimic the colon cancer microenvironment, and in athymic, irradiated nude mice through bioluminescence of tumor growth. In aggregate, our studies have the means to unravel new pathways of regulation of the Ras and c-myc oncogenes by the Let-7a3 and Let-7b microRNAs in colon cancer, especially where sporadic colorectal cancers (chromosomal instability pathway) do not harbor Ras mutations.

Public Health Relevance

Colorectal cancer (CRC) serves as a paradigm for the investigation of basic mechanisms and translation into novel chemopreventive, diagnostic and therapeutic strategies. The underlying pathogenesis of CRC may involve the Let-7a3 and Let-7b microRNAs, which in general are critical regulators of normal cellular processes to malignant transformation. Our studies hope to reveal new paradigms in CRC pathogenesis, and offer opportunities for exploiting this knowledge in novel diagnostics and therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056645-13
Application #
8282838
Study Section
Special Emphasis Panel (ZRG1-DIG-C (05))
Program Officer
Hamilton, Frank A
Project Start
2000-03-01
Project End
2013-08-31
Budget Start
2012-06-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$328,027
Indirect Cost
$119,756
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong et al. (2014) SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas. J Clin Invest 124:1636-45
Hamilton, Kathryn E; Noubissi, Felicite K; Katti, Prateek S et al. (2013) IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts. Carcinogenesis 34:2647-54
Madison, Blair B; Liu, Qi; Zhong, Xue et al. (2013) LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7. Genes Dev 27:2233-45
King, Catrina E; Cuatrecasas, Miriam; Castells, Antoni et al. (2011) LIN28B promotes colon cancer progression and metastasis. Cancer Res 71:4260-8
King, C E; Wang, L; Winograd, R et al. (2011) LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene 30:4185-93
Mongroo, Perry S; Noubissi, Felicite K; Cuatrecasas, Miriam et al. (2011) IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer Res 71:2172-82
Mongroo, Perry S; Rustgi, Anil K (2010) The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol Ther 10:219-22
Hanlon, Linda; Avila, Jacqueline L; Demarest, Renee M et al. (2010) Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res 70:4280-6
Rangiah, Kannan; Tippornwong, Montri; Sangar, Vineet et al. (2009) Differential secreted proteome approach in murine model for candidate biomarker discovery in colon cancer. J Proteome Res 8:5153-64
Vakoc, Christopher R; Wen, Yu-Ye; Gibbs, Richard A et al. (2009) Low frequency of MLL3 mutations in colorectal carcinoma. Cancer Genet Cytogenet 189:140-1

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