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Open Access Highly Accessed Research article

Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states

Aaron L Sarver1*, Amy J French2, Pedro M Borralho3, Venugopal Thayanithy4, Ann L Oberg5, Kevin AT Silverstein1, Bruce W Morlan5, Shaun M Riska5, Lisa A Boardman6, Julie M Cunningham2, Subbaya Subramanian4, Liang Wang2, Tom C Smyrk2, Cecilia MP Rodrigues3, Stephen N Thibodeau2 and Clifford J Steer78

Author Affiliations

1 Biostatistics and Informatics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA

2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

3 Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

4 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA

5 Department of Health Sciences Research, Division of Biomedical Informatics and Statistics, Mayo Clinic, Rochester, Minnesota, USA

6 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA

7 Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

8 Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA

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BMC Cancer 2009, 9:401  doi:10.1186/1471-2407-9-401

Published: 18 November 2009

Abstract

Background

Colon cancer arises from the accumulation of multiple genetic and epigenetic alterations to normal colonic tissue. microRNAs (miRNAs) are small, non-coding regulatory RNAs that post-transcriptionally regulate gene expression. Differential miRNA expression in cancer versus normal tissue is a common event and may be pivotal for tumor onset and progression.

Methods

To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR.

Results

Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes.

Conclusion

Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states.