Impact of microRNAs on regulatory networks and pathways in human colorectal carcinogenesis and development of metastasis.
Impact of microRNAs on regulatory networks and pathways in human colorectal carcinogenesis and development of metastasis.
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DOI：
10.1186/1471-2164-14-589
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发表时间：
2013-08-29
期刊：
影响因子：
4.4
通讯作者：
Zanovello P
中科院分区：
文献类型：
--
作者：
Pizzini S;Bisognin A;Mandruzzato S;Biasiolo M;Facciolli A;Perilli L;Rossi E;Esposito G;Rugge M;Pilati P;Mocellin S;Nitti D;Bortoluzzi S;Zanovello P
在结肠癌中，microRNAs(MiRNAs)的质变或异常表达主要见于原发肿瘤。肿瘤抑制因子miRNAs、肿瘤抑制因子miRNAs和转移受体的重叠不佳与结直肠癌进展的不同阶段有关。为了确定正常结肠粘膜、原发肿瘤和肝转移癌标本中miRNA和基因表达水平的变化，并将miRNAs分类为功能网络，本工作分析了46例患者158例的miRNA和基因表达谱。MiRNA和基因表达水平的大部分变化已经在原发肿瘤中表现出来，而这些水平在随后的原发肿瘤到转移的转变中几乎保持稳定。此外，比较正常组织、肿瘤和转移，我们没有观察到一般的损伤或miRNA生物合成的任何增加。虽然只有很少的mRNAs在原发结直肠癌和肝转移癌之间有差异表达，但miRNA表达谱可以很好地区分原发癌和转移癌，包括miR-10b、miR-210和miR-708的差异表达。在肿瘤进展过程中被调控的82个miRNAs中，有22个参与了EMT。定量逆转录聚合酶链式反应证实miR-150和miR-10b在原发灶和转移灶中的表达均低于正常粘膜，在转移灶中的表达水平低于原发灶。与正常和原发肿瘤相比，miR-201在转移性肿瘤中的表达上调也得到证实。一项考虑差异表达miRNAs的初步生存分析表明，miR-10b在转移中的表达与患者生存之间可能存在联系。通过整合miRNA和靶基因表达数据，我们确定了一组相互连接的miRNAs，这些miRNAs被组织成子网络，包括与差异表达基因的几种调控关系。关键的调控相互作用得到了实验验证。发现了涉及miRNAs和转录因子的特定混合回路，值得进一步研究。首次鉴定了miR-182对ENTPD5基因的抑制活性，并在一组独立的样本中得到了证实。使用CRC miRNA和基因表达谱的大型数据集，我们描述了miRNA组在调节基因表达方面的相互作用，这反过来又影响到对肿瘤发展至关重要的调节途径。
Qualitative alterations or abnormal expression of microRNAs (miRNAs) in colon cancer have mainly been demonstrated in primary tumors. Poorly overlapping sets of oncomiRs, tumor suppressor miRNAs and metastamiRs have been linked with distinct stages in the progression of colorectal cancer. To identify changes in both miRNA and gene expression levels among normal colon mucosa, primary tumor and liver metastasis samples, and to classify miRNAs into functional networks, in this work miRNA and gene expression profiles in 158 samples from 46 patients were analysed. Most changes in miRNA and gene expression levels had already manifested in the primary tumors while these levels were almost stably maintained in the subsequent primary tumor-to-metastasis transition. In addition, comparing normal tissue, tumor and metastasis, we did not observe general impairment or any rise in miRNA biogenesis. While only few mRNAs were found to be differentially expressed between primary colorectal carcinoma and liver metastases, miRNA expression profiles can classify primary tumors and metastases well, including differential expression of miR-10b, miR-210 and miR-708. Of 82 miRNAs that were modulated during tumor progression, 22 were involved in EMT. qRT-PCR confirmed the down-regulation of miR-150 and miR-10b in both primary tumor and metastasis compared to normal mucosa and of miR-146a in metastases compared to primary tumor. The upregulation of miR-201 in metastasis compared both with normal and primary tumour was also confirmed. A preliminary survival analysis considering differentially expressed miRNAs suggested a possible link between miR-10b expression in metastasis and patient survival. By integrating miRNA and target gene expression data, we identified a combination of interconnected miRNAs, which are organized into sub-networks, including several regulatory relationships with differentially expressed genes. Key regulatory interactions were validated experimentally. Specific mixed circuits involving miRNAs and transcription factors were identified and deserve further investigation. The suppressor activity of miR-182 on ENTPD5 gene was identified for the first time and confirmed in an independent set of samples. Using a large dataset of CRC miRNA and gene expression profiles, we describe the interplay of miRNA groups in regulating gene expression, which in turn affects modulated pathways that are important for tumor development.
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