Sun Min, Song Haibin, Wang Shuyi, Zhang Chunxiao, Zheng Liang, Chen Fangfang, Shi Dongdong, Chen Yuanyuan, Yang Chaogang, Xiang Zhenxian, Liu Qing, Wei Chen, Xiong Bin
Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, 430071, Wuhan, People's Republic of China.
J Hematol Oncol. 2017 Mar 29;10(1):79. doi: 10.1186/s13045-017-0445-8.
With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a "pre-laboratory" integrated analysis to expedite effective precision medicine and translational research. Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear.
In this study, we performed an integrated analysis of seven CRC miRNAs expression datasets. The expression of miR-195 was validated in The Cancer Genome Atlas (TCGA) datasets, and an independent validation sample cohort. Colon cancer cells were transfected with miR-195 mimic and inhibitor, after which cell proliferation, colony formation, migration, invasion, and dual luciferase reporter were assayed. Xenograft mouse models were used to determine the role of miR-195 in CRC tumorigenicity in vivo.
Four downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting. CRC patients with a decreased level of miR-195-5p in tumor tissues had significantly shortened survival as revealed by the TCGA colon adenocarcinoma (COAD) dataset and our CRC cohort. Overexpression of miR-195-5p in DLD1 and HCT116 cells repressed cell growth, colony formation, invasion, and migration. Inhibition of miR-195-5p function contributed to aberrant cell proliferation, migration, invasion, and epithelial mesenchymal transition (EMT). We identified miR-195-5p binding sites within the 3'-untranslated region (3'-UTR) of the human yes-associated protein (YAP) mRNA. YAP1 expression was downregulated after miR-195-5p treatment by qRT-PCR analysis and western blot.
Four downregulated miRNAs were shown to be prime candidates for a panel of biomarkers with sufficient diagnostic accuracy for CRC in a clinical setting. Our integrated microRNA profiling approach identified miR-195-5p independently associated with prognosis in CRC. Our results demonstrated that miR-195-5p was a potent suppressor of YAP1, and miR-195-5p-mediated downregulation of YAP1 significantly reduced tumor development in a mouse CRC xenograft model. In the clinic, miR-195-5p can serve as a prognostic marker to predict the outcome of the CRC patients.
由于结直肠癌（CRC）微小RNA（miRNA）表达数据一直存在不一致性，转向纳入“实验室前”综合分析对于加快有效的精准医学和转化研究至关重要。人miR-195（hsa-miRNA-195）的异常表达已在多种癌症中被观察到，它被认为是一种具有临床意义的miRNA，但其在结直肠癌中的作用仍不清楚。
在本研究中，我们对七个结直肠癌miRNA表达数据集进行了综合分析。miR-195的表达在癌症基因组图谱（TCGA）数据集和一个独立的验证样本队列中得到验证。用miR-195模拟物和抑制剂转染结肠癌细胞，然后检测细胞增殖、集落形成、迁移、侵袭和双荧光素酶报告基因。使用异种移植小鼠模型来确定miR-195在结直肠癌体内致瘤性中的作用。
四个下调的miRNA（hsa-let-7a、hsa-miR-125b、hsa-miR-145和hsa-miR-195）被证明可能是临床环境中有用的诊断标志物。TCGA结肠腺癌（COAD）数据集和我们的结直肠癌队列显示，肿瘤组织中miR-195-5p水平降低的结直肠癌患者生存期显著缩短。miR-195-5p在DLD1和HCT116细胞中的过表达抑制了细胞生长、集落形成、侵袭和迁移。抑制miR-195-5p功能导致细胞异常增殖、迁移、侵袭和上皮间质转化（EMT）。我们在人Yes相关蛋白（YAP）mRNA的3'非翻译区（3'-UTR）内鉴定到了miR-195-5p结合位点。通过qRT-PCR分析和蛋白质印迹法发现，miR-195-5p处理后YAP1表达下调。
四个下调的miRNA被证明是一组生物标志物的主要候选者，在临床环境中对结直肠癌具有足够的诊断准确性。我们的综合微小RNA谱分析方法确定了miR-195-5p与结直肠癌的预后独立相关。我们的结果表明，miR-195-5p是YAP1的有效抑制剂，在小鼠结直肠癌异种移植模型中，miR-195-5p介导的YAP1下调显著减少了肿瘤发展。在临床上，miR-195-5p可作为预测结直肠癌患者预后的标志物。
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