N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration.
N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration.
复制标题
DOI：
10.1186/s13059-017-1224-0
复制
发表时间：
2017-05-24
期刊：
影响因子：
12.3
通讯作者：
Calin GA
中科院分区：
文献类型：
--
作者：
Rigoutsos I;Lee SK;Nam SY;Anfossi S;Pasculli B;Pichler M;Jing Y;Rodriguez-Aguayo C;Telonis AG;Rossi S;Ivan C;Catela Ivkovic T;Fabris L;Clark PM;Ling H;Shimizu M;Redis RS;Shah MY;Zhang X;Okugawa Y;Jung EJ;Tsirigos A;Huang L;Ferdin J;Gafà R;Spizzo R;Nicoloso MS;Paranjape AN;Shariati M;Tiron A;Yeh JJ;Teruel-Montoya R;Xiao L;Melo SA;Menter D;Jiang ZQ;Flores ER;Negrini M;Goel A;Bar-Eli M;Mani SA;Liu CG;Lopez-Berestein G;Berindan-Neagoe I;Esteller M;Kopetz S;Lanza G;Calin GA
近年来，非编码RNA受到越来越多的关注，因为功能数据表明它们在关键的细胞过程中发挥着重要作用。N-BLR是灵长类特有的非编码长链RNA，调节上皮向间充质的转化，促进细胞迁移，增加结直肠癌的侵袭性。我们对两个独立的结直肠癌患者队列的数据进行了多变量分析，结果表明N-BLR的丰度与肿瘤分期、侵袭潜能和总体患者生存有关。通过体外和体内实验，我们发现N-BLR主要通过与E-钙粘蛋白和ZEB1的串扰促进迁移。我们发现这种串扰是由N-BLR转录本中包含的一个短~20个核苷酸-长的DNA基序吡克农介导的，并且是miR-200家族成员的靶标。根据这些发现，我们使用微阵列来研究其他含有吡克农的基因组基因座的表达模式。我们发现，在结直肠癌和慢性淋巴细胞白血病的健康和病变组织中，有多个这样的基因座存在差异转录。此外，我们还发现了几个新的基因座，它们的表达与结直肠癌患者的总体生存相关。灵长类特有的N-BLR是结直肠癌转移复杂机制的一个新的分子贡献者，也是一种潜在的新的疾病生物标记物。在N-BLR中存在功能性吡克农，以及相关发现，人类基因组中更多含有吡克农的基因组位点表现出组织特异性和疾病特异性表达，这表明有可能出现另一类灵长类动物特异性的生物标志物和治疗靶点。本文的在线版本(doi：10.1186/s13059-017-1224-0)包含补充材料，授权用户可以使用。
Non-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion. We performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients’ overall survival. The primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific. The online version of this article (doi:10.1186/s13059-017-1224-0) contains supplementary material, which is available to authorized users.