Colon adenocarcinoma is a leading cause of cancer mortality worldwid and accounts for approximately 50,000 deaths annually in the United States. There is a need to improve early detection screening methods for colorectal cancer (CRC). If detected early, CRC is highly curable. Colonoscopies are a reliable and accurate screening tool but their high cost and invasiveness lead to reduced screening rates. On the other hand, faecal occult blood tests (FOBTs) are less invasive, less expensive, have even been shown to reduce deaths caused by CRC;1 but the limited sensitivity and specificity of FOBT make it a less than ideal screening method for detecting CRC. Many researchers are trying to identify non-invasive screening methodologies, such as blood tests or faecal DNA tests,2 to improve early detection of CRC to reduce the health burden of this disease. Previous work investigated measuring circulating, tumour-associated DNA or mRNA as screens for various cancers with some success. Levels of circulating microRNAs have potential as diagnostic biomarkers for CRC. We have performed primary research and written commentaries on this topic. We used quantitative reverse transcription-polymerase chain reaction to measure microRNAs in plasma samples from colon cancer patients. We found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer. Therefore, we propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis. We also investigated functional roles of specific genes in mouse models of colon cancer to find that genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally, IGF-1 inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most do not survive, making it difficult to study how genetic ablation of IGF-1 affects colon tumorigenesis. To test the hypothesis that inhibition of IGF-1 prevents colon tumorigenesis, we utilized a preexisting mouse model containing a deletion of the igf1 gene in the liver through a Cre/loxP system. These liver-specific IGF-1 deficient (LID) mice display a 5075% reduction in circulating IGF-1 levels. We conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice had a significant inhibition of colon tumor multiplicity in the proximal area of the colon compared to their wild-type littermates. We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Schetter, Aaron J; Okayama, Hirokazu; Harris, Curtis C (2012) The role of microRNAs in colorectal cancer. Cancer J 18:244-52
Ryan, Brid M; McClary, Andrew C; Valeri, Nicola et al. (2012) rs4919510 in hsa-mir-608 is associated with outcome but not risk of colorectal cancer. PLoS One 7:e36306
Schetter, Aaron J; Harris, Curtis C (2011) Alterations of microRNAs contribute to colon carcinogenesis. Semin Oncol 38:734-42
Cheng, Hanyin; Zhang, Lina; Cogdell, David E et al. (2011) Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS One 6:e17745
Volinia, Stefano; Galasso, Marco; Costinean, Stefan et al. (2010) Reprogramming of miRNA networks in cancer and leukemia. Genome Res 20:589-99
Schetter, Aaron J; Nguyen, Giang Huong; Bowman, Elise D et al. (2009) Association of inflammation-related and microRNA gene expression with cancer-specific mortality of colon adenocarcinoma. Clin Cancer Res 15:5878-87
Schetter, Aaron J; Harris, Curtis C (2009) Plasma microRNAs: a potential biomarker for colorectal cancer? Gut 58:1318-9
Olivo-Marston, Susan E; Hursting, Stephen D; Lavigne, Jackie et al. (2009) Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. Mol Carcinog 48:1071-6