microRNA-451a regulates colorectal cancer radiosensitivity

Abstract

2Colorectal cancer (CRC) is a leading cause of cancer-related death. The responses of CRC to standard of care adjuvant therapies such as radiation or chemotherapy are poorly understood. MicroRNAs (miRs) are small non-coding RNAs that affect gene expression programs in cells by downregulating specific mRNAs. In this study, we discovered a set of microRNAs upregulated rapidly in response to a single 2 Gy dose fraction of γ-radiation in a mouse colorectal carcinoma xenograft model. The most upregulated candidate in our signature, miR-451a inhibits tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes-CAB39, EMSY, MEX3C and EREG as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was decreased with tumor stage in a small subset of CRC patients. Finally, analysis of a TCGA colorectal cancer dataset reveals that the CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients and correlates with poorer overall survival. Taken together, our data indicates miR451a influences the radiation sensitivity of colorectal carcinomas.

Understanding and Resetting Radiation Sensitivity in Rectal Cancer

“…1). Prior data demonstrated significant influence of miR-451a in colorectal cancer in vitro and in vivo models 24 (see Supplementary Figures 1, 2, 3, http://links.lww.com/SLA/B286) miR-451a was validated in our cohort out of the four upregulated mIRs shown above. Exploration of posttreatment tissue was completed, using qPCR.…”

“…22 Patients with increased CAB39 and EMSY are shown to have upregulated in a number of signaling pathways, including RAF kinases and SHP2 enzymes. 22 We have demonstrated miR-451a directly binds and downregulates CAB39 and EMSY 24 (see Supplementary Figure 4, http:// links.lww.com/SLA/B286). We inhibited RAF and SHP2 in HCT-116 cells reversetransfected with anti-miR451a.…”

“…Our prior in vitro and in vivo models demonstrated miR-451a directly binds and downregulates CAB39 and EMSY 24 (see Supplementary Figure 4, http:// links.lww.com/SLA/B286). These 2 proteins are expressed in 14% and 6% of CRC, which was associated with worse survival.…”

“…We have shown miR-451a expression improves radiation treatment response within the in vivo and in vitro models. 24 We are the first to report on its predictive value in the setting of radiation sensitivity in rectal cancer. We aimed to reproduce these findings in the plasma of our cohort, as prior reports have identified a liquid biomarker to detect colorectal adenomas.…”

Diagnostic and Prognostic Value of miR-451 Expression in Colorectal Cancer: A Meta-Analysis

“…In addition, miR-451 is related to the inhibition of human CRC Cells via the downregulation of the Pi3k/Akt pathway [34]. Interestingly, it has been found that miR-451a affects the radiation sensitivity of colorectal carcinomas [35]. Taken together, these findings indicate that miR-451 could play a role in the development and progression of CRC, therefore, it could be a novel biomarker associated with CRC.…”