Abstract
microRNA (miRNA) based biomarkers have unique advantages due to their critical regulatory function, superior stability, and relatively small number compared to mRNAs. A number of miRNAs play key roles in colon cancer stem cell chemoresistance and have clinical potential as prognostic biomarkers. The purpose of this study is to systematically validate the prognostic potential of miRNAs in colorectal cancer. In this study, we validated the prognostic potential of a panel of miRNAs using 205 stage II, III, and IV colorectal cancer specimens by qRT-PCR analysis. We cross validated our results using The Cancer Genome Atlas (TCGA) database. Many of the miRNAs we investigated have been functionally validated to be important in contributing to chemoresistance to 5-fluorouracil (5-FU) based chemotherapy. We determined that miR-16 is the most consistent miRNA for expression normalization in colorectal cancer. We have validated several miRNAs (miR-15b, miR-215, miR-145, miR-192, let-7g) that are significantly associated with progression free survival (PFS) and/or overall survival (OS) of colorectal cancer patients independent of tumor stage and age at diagnosis. These 5 miRNAs are significantly associated with OS of colorectal cancer even after tumor location (left side vs. right side) is adjusted for. Furthermore, the prognostic value of let-7g for overall survival was independently validated using the RNA-Seq results from TCGA colorectal cancer database. These results, taken together, establish a solid foundation towards miRNA based precision management of colorectal cancer.
Highlights
Colorectal cancer is one of the leading causes of cancer related death in the United States with more than 50,000 deaths every year [1]
Based on the expression profiles of these genes from 200 colorectal cancer samples, we show that miR-16 is the best housekeeping gene for miRNA expression analysis (Figure 1)
We evaluated the prognostic potential of miRNAs in colorectal cancer based on 200 patient samples with clinical outcome follow up information
Summary
Colorectal cancer is one of the leading causes of cancer related death in the United States with more than 50,000 deaths every year [1]. The current 5-year survival rate for stage II colorectal cancer patients is between 70-80%. As for advanced stage III and IV colorectal cancer patients, despite years of effort, there is still a lack of highly reliable prognostic biomarkers to determine which patients will benefit from chemotherapy. In both early and advanced stages of colorectal cancers, there is clearly an unmet need for biomarkers for better clinical management
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