microRNA-451a 通过调控辐射应答影响结直肠癌细胞增殖。
microRNA-451a regulates colorectal cancer proliferation in response to radiation.
机构信息
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
出版信息
BMC Cancer. 2018 May 3;18(1):517. doi: 10.1186/s12885-018-4370-1.
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.
背景
结直肠癌（CRC）是癌症相关死亡的主要原因。CRC 对标准护理辅助治疗（如化疗和放疗）的生物学反应了解甚少。已经表明 microRNAs（miRs）会影响 CRC 的进展和转移。因此，我们假设特定的 miR 调节 CRC 对放化疗的反应。
方法
在这项研究中，我们使用 miR 表达谱分析发现了一组在小鼠结直肠癌细胞模型中对单次 2Gy 剂量或 10Gy 剂量 γ 辐射快速上调的 microRNAs。我们使用二维和三维细胞增殖测定和集落形成测定中的增益和失活功能研究来了解我们分析中 top miR 候选物的作用。我们使用学生 t 检验进行简单比较，使用双因素方差分析评估显著性。
结果
在我们的特征中，早期时间点上调最明显的候选物 miR-451a 抑制肿瘤细胞增殖，并在较长时间的培养中减弱存活分数。相反，抑制 miR-451a 增加了肿瘤细胞的增殖、肿瘤球形成和存活分数。使用生物信息学方法，我们鉴定出 CAB39、EMSY、MEX3C 和 EREG 这四个基因是 miR-451a 的靶基因。miR-451a 的转染降低了这些靶基因的 mRNA 和蛋白水平。重要的是，与没有反应的患者相比，在对放化疗有部分反应的一小部分直肠癌患者中，miR-451a 表达较高，而 CAB39 和 EMSY 水平较低。最后，对 TCGA 结直肠癌数据集的分析表明，在大量 CRC 患者中，CAB39 和 EMSY 在蛋白水平上上调。较高的 CAB39 和 EMSY 水平与较差的总生存期相关。
结论
综上所述，我们的数据表明 miR-451a 是由辐射诱导的，可能通过 CAB39 和 EMSY 途径影响结直肠癌细胞的增殖。
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