RT Journal Article
SR Electronic
T1 microRNA-451a regulates colorectal cancer radiosensitivity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 136234
DO 10.1101/136234
A1 Rebecca Ruhl
A1 Shushan Rana
A1 Katherine Kelley
A1 Cristina Espinosa-Diez
A1 Clayton Hudson
A1 Christian Lanciault
A1 Charles R Thomas, Jr
A1 Liana V Tsikitis
A1 Sudarshan Anand
YR 2017
UL http://biorxiv.org/content/early/2017/05/09/136234.abstract
AB Colorectal 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 miR-451a influences the radiation sensitivity of colorectal carcinomas.