microRNA-451a regulates colorectal cancer proliferation in response to radiation

Abstract

BackgroundColorectal 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.MethodsIn 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.ResultsThe 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.ConclusionsTaken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4370-1) contains supplementary material, which is available to authorized users.

miR‐155‐5p and miR‐760 mediate radiation therapy suppressed malignancy of non‐small cell lung cancer cells

“…However, overexpression of miR‐21 can promote the radiation resistance of NSCLC cells . In colorectal cancer cells, miR‐451a can regulate the cell proliferation in response to radiation . It has been reported that miR‐124 can enhance the radiation‐induced apoptosis of NSCLC cells via inhibition of STAT3 .…”

“…It has been reported that radiation greater than 5 Gy can significantly inhibit the proliferation of NSCLC cells . Our data showed that the radiation of 2 Gy, which had no significant effect on cell proliferation , can significantly inhibit the wound healing of A549 (Fig. a) and H460 (Fig.…”

MicroRNA Profiling of Exosomes Derived from Red Blood Cell Units: Implications in Transfusion-Related Immunomodulation

“…Till date, several researches have demonstrated that miR-451a could inhibit the proliferation and differentiation of benign and malignant tumour cell and also affect the chemosensitivity of the tumour cells. Moreover, miR-451a in extracellular vesicles has been reported to influence the functions of immune cells, such as macrophages and dendritic cells [28,[33][34][35][36]. Hence, in the present study the predominantly enriched miR-451a in exosomes may be speculated to act as an important mediator in TRIM.…”

miR‐451a inhibits cancer growth, epithelial‐mesenchymal transition and induces apoptosis in papillary thyroid cancer by targeting PSMB8

“…Several studies have reported the cancer suppressor activity of miR‐451a in other cancer types . miR‐451a was reported to inhibit aggressiveness features of lung squamous cell cancer by targeting KIF2A .…”

“…Several studies have reported the cancer suppressor activity of miR-451a in other cancer types. [21][22][23] miR-451a was reported to inhibit aggressiveness features of lung squamous cell cancer by targeting KIF2A. 24 In colorectal cancer, miR-451a was reported to inhibit proliferation and increase apoptosis by targeting BAP31.…”