microRNA-451a regulates colorectal cancer proliferation in response to radiation
Autor: | Christian Lanciault, Rebecca Ruhl, Charles R. Thomas, Shushan Rana, Katherine A. Kelley, V. Liana Tsikitis, Sudarshan Anand, Clayton Hudson, Cristina Espinosa-Diez |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer medicine.medical_treatment Datasets as Topic Metastasis Mice 0302 clinical medicine Surgical oncology Mice Inbred BALB C Nuclear Proteins Chemoradiotherapy Transfection lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens microRNAs Neoplasm Proteins Up-Regulation Radiation therapy Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Female Colorectal Neoplasms Research Article Signal Transduction Mice Nude Biology lcsh:RC254-282 03 medical and health sciences Downregulation and upregulation microRNA Genetics medicine Animals Humans CAB39 Adaptor Proteins Signal Transducing Cell Proliferation EMSY Gene Expression Profiling Calcium-Binding Proteins HCT116 Cells medicine.disease Survival Analysis Xenograft Model Antitumor Assays Repressor Proteins Gene expression profiling 030104 developmental biology Cancer research |
Zdroj: | BMC Cancer BMC Cancer, Vol 18, Iss 1, Pp 1-9 (2018) |
ISSN: | 1471-2407 |
Popis: | Background Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. Methods In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student’s T-tests for simple comparisons and two-factor ANOVA for evaluating significance. Results The most upregulated candidate at early time points in our signature, miR-451a inhibited 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 high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Conclusions Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways. Electronic supplementary material The online version of this article (10.1186/s12885-018-4370-1) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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