Inflammatory genes and microRNAs have roles in colon carcinogenesis;therefore, they may provide useful biomarkers for colon cancer. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined microRNA-21 expression. Quantitative RTPCR measured the expression of 23 inflammatory genes in colon adenocarcinomas and adjacent noncancerous tissues from 196 patients. These data were used to develop models for cancer-specific mortality on a training cohort (n=57) and this model was tested in both a test (n=56) and validation (n=83) cohort. Expression data for microRNA-21 was available for these patients and was compared to and combined with inflammatory gene expression. PRG1, IL-10, CD68, IL-23a, and IL-12a expression in noncancerous tissue and PRG1, ANXA1, IL-23a, IL-17a, FOXP3, and HLA-DRA expression in tumor tissues were associated with poor prognosis based on Cox regression (Z score greater than 1.5) and were used to generate inflammatory risk score (IRS). IRS was associated with cancer-specific mortality in the training, test (P=0.01) and validation (P=0.02) cohorts. This association was strong for stage II cases (P=0.002). microRNA-21 expression was associated with IL-6, IL-8, IL-10, IL-12a and NOS2a, providing evidence that the function of this microRNA and these inflammatory genes are linked. Both IRS and microRNA-21 expression were independently associated with cancer-specific mortality, including stage II patients alone. IRS and microRNA-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high risk patients. We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enables us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression on normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Non malignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs, hsa-miR 103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of the miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010878-03
Application #
8157515
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2010
Total Cost
$740,964
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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