MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer
MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer
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DOI：
10.1101/gad.1820109
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发表时间：
2009-09-15
影响因子：
10.5
通讯作者：
Hanahan, Douglas
中科院分区：
文献类型：
--
作者：
Olson, Peter;Lu, Jun;Hanahan, Douglas
虽然microRNAs(MiRs)在肿瘤中的表达改变已经被很好地记录下来，但miR转录组如何与肿瘤进展相交仍不清楚。通过对miR转录组的分析，我们确定了miR的表达特征与肿瘤发生过程中的步骤以及在典型的癌症小鼠模型中获得标志性能力的步骤有关。转移瘤和少见的原发肿瘤共享一个明显的miR征象，暗示转移性肿瘤具有离散的谱系。MiR-200家族在转移性肿瘤和MET样原发肿瘤中表达强烈下调，从而缓解了间充质转录因子ZEB1的抑制，后者反过来抑制E-钙粘素。临床批准的血管生成抑制剂的治疗使原发肿瘤的血管生成标志miRs正常化，同时改变了与肝转移相似的转移标志miRs的表达，表明它们通过增强转移参与了对抗血管生成治疗的适应性抵抗。在小鼠模型中，许多与特定阶段和标志能力相关的miR变化在人类肿瘤中也有类似的变化，包括同源胰腺神经内分泌肿瘤，这意味着一般性。
While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.