Abstract
Colorectal cancer (CRC) screening tests often have a trade-off between efficacy and patient acceptability/cost. Fecal tests (occult blood, methylation) engender excellent patient compliance but lack requisite performance underscoring the need for better population screening tests. We assessed the utility of microRNAs (miRNAs) as markers of field carcinogenesis and their potential role for CRC screening using the azoxymethane (AOM)-treated rat model. We found that 63 miRNAs were upregulated and miR-122, miR-296-5p and miR-503# were downregulated in the uninvolved colonic mucosa of AOM rats. We monitored the expression of selected miRNAs in colonic biopsies of AOM rats at 16 weeks and correlated it with tumor development. We noted that the tumor bearing rats had significantly greater miRNA modulation compared to those without tumors. The miRNAs showed good diagnostic performance with an area under the receiver operator curve (AUROC) of >0.7. We also noted that the miRNA induction in the colonic mucosa was mirrorred in the mucus layer fecal colonocytes isolated from AOM rat stool and the degree of miRNA induction was greater in the tumor bearing rats compared to those without tumors. Lastly, we also noted significant miRNA modulation in the Pirc rats- the genetic model of colon carcinogenesis, both in the uninvolved colonic mucosa and the fecal colonocytes. We thus demonstrate that miRNAs are excellent markers of field carcinogenesis and could accurately predict future neoplasia. Based on our results, we propose an accurate, inexpensive, non-invasive miRNA test for CRC risk stratification based on rectal brushings or from abraded fecal colonocytes.
Highlights
Colorectal cancers evolve through a defined sequence of cellular and morphological events which is choreographed by dysregulation of,15 critical molecular pathways [1]
We demonstrate that a number of microRNAs were dysregulated in the predysplastic colonic mucosa
The striking finding was that were these micro RNAs dysregulated in cancer, and at the premalignant time point and predict which AOM-treated animals would develop tumors in the future making this potentially relevant to colorectal cancer screening
Summary
Colorectal cancers evolve through a defined sequence of cellular and morphological events (hyperproliferative, nondysplastic epitheliumRadenomaRcarcinoma) which is choreographed by dysregulation of ,15 critical molecular pathways [1] These alterations occur through both endogenous (genetic, secondary bile salts, etc.) and exogenous (diet, smoking) insults which are diffuse (impacting the whole colon) leading to the well established concept of field carcinogenesis (aka field of injury, field effect, field defect). Field carcinogenesis is used as a modality for risk stratification using a variety of biomarkers at the macroscopic (adenomas, aberrant crypt foci), microscopic (apoptosis/proliferation) and histologically normal (gene expression, proteomics etc) level This provides critical insights into early events in carcinogenesis especially in epigenetic silencing of tumor suppressor genes.
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