Differential MicroRNA Expression in Colorectal Cancer Patients Presenting with Synchronous Hepatic Metastases
Chad J Ellermeier, Kelly Cleveland, Alexander S Brodsky, Murray Resnick. Rhode Island Hospital/Warren Alpert Medical School of Brown University, Providence, RI
Background: MicroRNAs (miRNAs) are a class of highly conserved ∼22-nucleotide single-stranded RNAs that bind complementary sequences of messenger RNA (mRNA) and induce translation repression and/or mRNA degradation. While previous publications have described associations between specific miRNAs and colorectal cancer (CRC) metastases, there are still many aspects of RNA regulators of metastatic spread that are unexplored. We examined the differential expression of miRNAs in CRC primary tumors with synchronous liver metastases and analyzed miRNA expression correlation with patient survival.
Design: Thirty-one colorectal cancer (CRC) cases selected from the Lifespan Hospital System archives were analyzed. Portions of both colonic and liver formalin fixed paraffin embedded tissue sections were laser capture microdissected. RNA was extracted and miRNAs were then amplified using qRT-PCR. Individual miRNAs were identified using array cards with miRNA expression quantitated using qRT-PCR. Expression in primary tumors, liver metastases, and differential expression were tested for association with length of survival.
Results: 20 different miRNAs showed significant differential expression between CRC primary tumors and liver metastases. Of these 20, 6 (miR-210, miR-133b, miR-708, miR-548a-3p, miR-204, miR-618) were confirmed by quantitative PCR (paired t-test, p<0.05). Analysis reveals that the change in expression levels of miR-210 (mean=4.2 fold, median=2.5 fold, standard deviation=7.1) and miR-133b (mean =76.1 fold, median=0.2 fold, standard deviation=369.3) between primary and metastatic tumors are significantly associated with overall survival, with both miRNAs showing increased expression in liver metastases. Increased miR-133b and miR-210 expression in liver metastases when compared to primary CRC tumor showed a hazard ratio of 1.9 (p=0.04 with Cox proportional hazards model: 95% confidence levels; 1.03 to 3.7). miR-210 expression also correlates with tumor necrosis as identified by microscopic morphology.
Conclusions: This is the first study to show association of differential expression of miR-210 and decreased length of survival. While miR-133b was previously shown to be downregulated in colorectal cancers, our study shows that, despite the low absolute expression of miR-133b in both primary CRC tumor and liver metastases, a relative increase in expression in metastastic disease is associated with significantly decreased overall survival.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 239, Tuesday Morning