Understanding and Resetting Radiation Sensitivity in Rectal Cancer

Katherine A. Kelley, Rebecca A. Ruhl, Shushan R. Rana, Elizabeth Dewey, Cristina Espinosa, Charles Thomas, Robert Martindale, Sudarshan Anand, Vassiliki Tsikitis

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE:: The aim of the study was to explore specific microRNAs (miRs) in rectal cancer that would predict response to radiation and identify target pathways that may be exploited for neoadjuvant therapies. SUMMARY BACKGROUND DATA:: Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers. METHODS:: Forty-five rectal cancer patients, partial responders (PR = 18), nonresponders (NR = 13), and complete responders (CR = 14) to CRT, as defined by a tumor regression score, were examined. miRs differentially expressed, using NanoString microArray profiling, were validated with qPCR. We quantified 1 miR and its downstream targets in patient samples. Chemosensitivity was measured in HCT-116, a human colorectal carcinoma cell line, using inhibitors of SHP2 and RAF. RESULTS:: miR-451a, 502-5p, 223-3p, and 1246 were the most upregulated miRs (>1.5-fold change) in a NanoString profiling miR panel. qPCR revealed a decrease in expression of miR-451a in NRs. EMSY and CAB39, both downstream targets of miR-451a and involved in carcinogenesis (shown in TCGA) were increased in NRs (qPCR). Both targets are associated with worse survival in colorectal cancer. Inhibition of miR-451a in HCT-116 cells significantly decreased cell proliferation with treatment of SHP2 and RAF inhibitors. CONCLUSIONS:: An integrated analysis of rectal cancer miRs may yield biomarkers of radioresistance and offer treatment targets for resensitization.

Original languageEnglish (US)
JournalAnnals of Surgery
DOIs
StateAccepted/In press - Jul 24 2017

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Radiation Tolerance
Rectal Neoplasms
MicroRNAs
Chemoradiotherapy
Colorectal Neoplasms
HCT116 Cells
Neoadjuvant Therapy
Survival
Neoplasms
Carcinogenesis
Biomarkers
Cell Proliferation
RNA
Radiation
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Surgery

Cite this

Understanding and Resetting Radiation Sensitivity in Rectal Cancer. / Kelley, Katherine A.; Ruhl, Rebecca A.; Rana, Shushan R.; Dewey, Elizabeth; Espinosa, Cristina; Thomas, Charles; Martindale, Robert; Anand, Sudarshan; Tsikitis, Vassiliki.

In: Annals of Surgery, 24.07.2017.

Research output: Contribution to journalArticle

Kelley, Katherine A. ; Ruhl, Rebecca A. ; Rana, Shushan R. ; Dewey, Elizabeth ; Espinosa, Cristina ; Thomas, Charles ; Martindale, Robert ; Anand, Sudarshan ; Tsikitis, Vassiliki. / Understanding and Resetting Radiation Sensitivity in Rectal Cancer. In: Annals of Surgery. 2017.
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AU - Espinosa, Cristina

AU - Thomas, Charles

AU - Martindale, Robert

AU - Anand, Sudarshan

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N2 - OBJECTIVE:: The aim of the study was to explore specific microRNAs (miRs) in rectal cancer that would predict response to radiation and identify target pathways that may be exploited for neoadjuvant therapies. SUMMARY BACKGROUND DATA:: Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers. METHODS:: Forty-five rectal cancer patients, partial responders (PR = 18), nonresponders (NR = 13), and complete responders (CR = 14) to CRT, as defined by a tumor regression score, were examined. miRs differentially expressed, using NanoString microArray profiling, were validated with qPCR. We quantified 1 miR and its downstream targets in patient samples. Chemosensitivity was measured in HCT-116, a human colorectal carcinoma cell line, using inhibitors of SHP2 and RAF. RESULTS:: miR-451a, 502-5p, 223-3p, and 1246 were the most upregulated miRs (>1.5-fold change) in a NanoString profiling miR panel. qPCR revealed a decrease in expression of miR-451a in NRs. EMSY and CAB39, both downstream targets of miR-451a and involved in carcinogenesis (shown in TCGA) were increased in NRs (qPCR). Both targets are associated with worse survival in colorectal cancer. Inhibition of miR-451a in HCT-116 cells significantly decreased cell proliferation with treatment of SHP2 and RAF inhibitors. CONCLUSIONS:: An integrated analysis of rectal cancer miRs may yield biomarkers of radioresistance and offer treatment targets for resensitization.

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