MicroRNAs and chromosome 22q in the colon

Summary

Principal Investigator: Anil Rustgi
Affiliation: University of Pennsylvania
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: ----------------2000 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. ncbi The genetics of hereditary colon cancer
    Anil K Rustgi
    Dapartment of Medicine Gastrointestinal, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 21:2525-38. 2007
  2. pmc LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
    Blair B Madison
    Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 27:2233-45. 2013
  3. pmc IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts
    Kathryn E Hamilton
    Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Carcinogenesis 34:2647-54. 2013
  4. pmc Identification of Lynch syndrome among patients with colorectal cancer
    Leticia Moreira
    Department of Gastroenterology, Hospital Clinic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Institut d Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
    JAMA 308:1555-65. 2012
  5. pmc Parvin-beta inhibits breast cancer tumorigenicity and promotes CDK9-mediated peroxisome proliferator-activated receptor gamma 1 phosphorylation
    Cameron N Johnstone
    Department of Medicine, Abramson Cancer Center, University of Pennsylvania, 600 Clinical Research Building, 415 Curie Blvd, Philadelphia, PA 19104, USA
    Mol Cell Biol 28:687-704. 2008
  6. pmc Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer
    Lin Zhang
    Center for Research on Early Detection and Cure of Ovarian Cancer and Gynecology, Department of Obstetrics, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:7004-9. 2008
  7. pmc Endothelin-3 stimulates survival of goblet cells in organotypic cultures of fetal human colonic epithelium
    Jiri Kalabis
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
    Am J Physiol Gastrointest Liver Physiol 295:G1182-9. 2008
  8. pmc Differential secreted proteome approach in murine model for candidate biomarker discovery in colon cancer
    Kannan Rangiah
    Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6160, USA
    J Proteome Res 8:5153-64. 2009
  9. pmc LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms
    C E King
    Gastroenterology Division and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Oncogene 30:4185-93. 2011
  10. pmc LIN28B promotes colon cancer progression and metastasis
    Catrina E King
    Gastroenterology Division and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Cancer Res 71:4260-8. 2011

Detail Information

Publications15

  1. ncbi The genetics of hereditary colon cancer
    Anil K Rustgi
    Dapartment of Medicine Gastrointestinal, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 21:2525-38. 2007
    ....
  2. pmc LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
    Blair B Madison
    Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 27:2233-45. 2013
    ..Let-7-dependent effects of LIN28B may supersede Let-7-independent effects on intestinal tissue growth. In summary, LIN28B can definitively act as an oncogene in the absence of canonical genetic alterations. ..
  3. pmc IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts
    Kathryn E Hamilton
    Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Carcinogenesis 34:2647-54. 2013
    ..Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis. ..
  4. pmc Identification of Lynch syndrome among patients with colorectal cancer
    Leticia Moreira
    Department of Gastroenterology, Hospital Clinic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Institut d Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
    JAMA 308:1555-65. 2012
    ..Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear...
  5. pmc Parvin-beta inhibits breast cancer tumorigenicity and promotes CDK9-mediated peroxisome proliferator-activated receptor gamma 1 phosphorylation
    Cameron N Johnstone
    Department of Medicine, Abramson Cancer Center, University of Pennsylvania, 600 Clinical Research Building, 415 Curie Blvd, Philadelphia, PA 19104, USA
    Mol Cell Biol 28:687-704. 2008
    ..Importantly, Parvin-beta suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-beta might influence breast cancer progression...
  6. pmc Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer
    Lin Zhang
    Center for Research on Early Detection and Cure of Ovarian Cancer and Gynecology, Department of Obstetrics, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:7004-9. 2008
    ..Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer...
  7. pmc Endothelin-3 stimulates survival of goblet cells in organotypic cultures of fetal human colonic epithelium
    Jiri Kalabis
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
    Am J Physiol Gastrointest Liver Physiol 295:G1182-9. 2008
    ..Our results demonstrate that ET3 is involved in regulating human colonic epithelial cell proliferation and survival, particularly for goblet cells, and may be an important component of colonic homeostasis...
  8. pmc Differential secreted proteome approach in murine model for candidate biomarker discovery in colon cancer
    Kannan Rangiah
    Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6160, USA
    J Proteome Res 8:5153-64. 2009
    ..Differential secretion into the serum was observed for several proteins when Apc(min) mice were compared with control mice. These findings were then confirmed by Western blot analysis...
  9. pmc LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms
    C E King
    Gastroenterology Division and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Oncogene 30:4185-93. 2011
    ..Our findings establish a new role for LIN28B in human colon cancer pathogenesis, and suggest LIN28B post-transcriptionally regulates LGR5 and PROM1 through a let-7-independent mechanism...
  10. pmc LIN28B promotes colon cancer progression and metastasis
    Catrina E King
    Gastroenterology Division and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Cancer Res 71:4260-8. 2011
    ..Together, our findings point to a function for LIN28B in promoting colon tumor pathogenesis, especially metastasis...
  11. pmc IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2
    Perry S Mongroo
    Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Cancer Res 71:2172-82. 2011
    ..35, P ≤ 0.0001) relative to adjacent normal mucosa. These findings indicate that IMP-1, interrelated with c-Myc, acts upstream of K-Ras to promote survival through a novel mechanism that may be important in colon cancer pathogenesis...
  12. pmc Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma
    Linda Hanlon
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601Spruce Street, Philadelphia, PA 19104, USA
    Cancer Res 70:4280-6. 2010
    ..Unexpectedly, the loss of Notch1 in this model resulted in increased tumor incidence and progression, implying that Notch1 can function as a tumor suppressor gene in PDAC...
  13. pmc The role of the miR-200 family in epithelial-mesenchymal transition
    Perry S Mongroo
    Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
    Cancer Biol Ther 10:219-22. 2010
    ....