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Understanding and Resetting Radiosensitivity in Rectal Cancer
Katherine A Kelley, Shushan Rana, Rebecca Ruhl, Christian Lanciault, John G Hunter, Charles R Thomas, Sudarshan Anand, Vassiliki L Tsikitis
Oregon Health and Sciences University, Portland, OR

Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. The Cancer Genome Atlas (TCGA) demonstrates that microRNAs (miRs) and their downstream targets modulate carcinogenesis and progression. We hypothesized specific miRs would predict response to radiation and identify targets that may be exploited for adjuvant therapies.
Thirty rectal cancer patients, partial responders (PR=12), non-responders (NR=12), and complete responders (CR=6) to CRT, as defined by the Mark-Ryne Tumor Regression Score, were examined. miRs differentially expressed by Nanostring technology were validated with qtPCR. We measured radiosensitivity and quantified downstream targets in HCT116 lines and patient samples.
miR-451a, 502-5p, 223-3p, and 1246 were the most upregulated miRs (>1.5 fold change) by Nanostring profiling. qtPCR revealed a significant decrease in expression of miR-451a in NRs. Transfecting a miR-451a mimic in HCT116 cell lines improved radiation response measured by surviving cell fraction, and decreased expression of all downstream targets. EMSY and CAB39, downstream targets of mir-451a involved in carcinogenesis (shown in TCGA) were increased in NRs (qtPCR). (Figure 1) Both targets are associated with worse survival in colorectal cancer. (Figure 2)
Mir-451a is a promising predictor of CRT response and manipulation of its downstream targets may restore radiosensitivity in NRs.

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