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


CONCLUSIONS
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.
Sarver
Aaron L
AL
Biostatistics and Informatics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. sarver@umn.edu
French
Amy J
AJ
Borralho
Pedro M
PM
Thayanithy
Venugopal
V
Oberg
Ann L
AL
Silverstein
Kevin A T
KA
Morlan
Bruce W
BW
Riska
Shaun M
SM
Boardman
Lisa A
LA
Cunningham
Julie M
JM
Subramanian
Subbaya
S
Wang
Liang
L
Smyrk
Tom C
TC
Rodrigues
Cecilia M P
CM
Thibodeau
Stephen N
SN
Steer
Clifford J
CJ
D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D053842:Microsatellite Instability; D009367:Neoplasm Staging; D020133:Reverse Transcriptase Polymerase Chain Reaction
D035683:MicroRNAs