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
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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