Rigoutsos Isidore, Lee Sang Kil, Nam Su Youn, Anfossi Simone, Pasculli Barbara, Pichler Martin, Jing Yi, Rodriguez-Aguayo Cristian, Telonis Aristeidis G, Rossi Simona, Ivan Cristina, Catela Ivkovic Tina, Fabris Linda, Clark Peter M, Ling Hui, Shimizu Masayoshi, Redis Roxana S, Shah Maitri Y, Zhang Xinna, Okugawa Yoshinaga, Jung Eun Jung, Tsirigos Aristotelis, Huang Li, Ferdin Jana, Gafà Roberta, Spizzo Riccardo, Nicoloso Milena S, Paranjape Anurag N, Shariati Maryam, Tiron Aida, Yeh Jen Jen, Teruel-Montoya Raul, Xiao Lianchun, Melo Sonia A, Menter David, Jiang Zhi-Qin, Flores Elsa R, Negrini Massimo, Goel Ajay, Bar-Eli Menashe, Mani Sendurai A, Liu Chang Gong, Lopez-Berestein Gabriel, Berindan-Neagoe Ioana, Esteller Manel, Kopetz Scott, Lanza Giovanni, Calin George A
Computational Medicine Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Genome Biol. 2017 May 24;18(1):98. doi: 10.1186/s13059-017-1224-0.
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.
近年来，非编码RNA越来越受到关注，因为功能数据表明它们在关键细胞过程中发挥重要作用。N-BLR是一种灵长类特异性长非编码RNA，可调节上皮-间质转化，促进细胞迁移，并增加结直肠癌侵袭。
我们对来自两个独立队列的结直肠癌患者数据进行了多变量分析，结果显示N-BLR的丰度与肿瘤分期、侵袭潜力和患者总生存期相关。通过体外和体内实验，我们发现N-BLR主要通过与E-钙黏蛋白和ZEB1相互作用促进迁移。我们表明，这种相互作用由一个致密子介导，致密子是N-BLR转录本中一个约20个核苷酸长的短DNA基序，是miR-200家族成员的作用靶点。基于这些发现，我们使用微阵列研究了其他含有致密子的基因组位点的表达模式。我们发现多个这样的位点在结直肠癌和慢性淋巴细胞白血病的健康组织和患病组织之间存在差异转录。此外，我们鉴定了几个新的位点，其表达与结直肠癌患者的总生存期相关。
灵长类特异性N-BLR是结直肠癌转移复杂机制的一个新的分子促成因素，也是该疾病潜在的新型生物标志物。N-BLR中存在功能性致密子，以及人类基因组中更多含有致密子的基因组位点表现出组织特异性和疾病特异性表达这一相关发现，提示了存在一类灵长类特异性的新型生物标志物和治疗靶点的可能性。
