Dataset Information

Understanding and Resetting Radiation Sensitivity in Rectal Cancer.

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.

SUBMITTER: Kelley KA

PROVIDER: S-EPMC7289057 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Understanding and Resetting Radiation Sensitivity in Rectal Cancer.

Kelley Katherine A KA Ruhl Rebecca A RA Rana Shushan R SR Dewey Elizabeth E Espinosa Cristina C Thomas Charles R CR Martindale Robert G RG Anand Sudarshan S Tsikitis Vassiliki L VL

Annals of surgery 20171001 4

<h4>Objective</h4>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.<h4>Summary background data</h4>Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers.<h4>Methods</h4>Forty-five rectal cancer patients, partial respond ...[more]

PMID: 28742699

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Project description:Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation-resistant disease is an obstacle for nearly 30-50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-β signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1α activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1's role on p53 and PGC-1α with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value = 10-9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers.

Dataset Information

Understanding and Resetting Radiation Sensitivity in Rectal Cancer.

Publications

Understanding and Resetting Radiation Sensitivity in Rectal Cancer.

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