N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration

Isidore Rigoutsos, Sang Kil Lee, Su Youn Nam, Simone Anfossi, Barbara Pasculli, Martin Pichler, Yi Jing, Cristian Rodriguez-Aguayo, Aristeidis G. Telonis, Simona Rossi, Cristina Ivan, Tina Catela Ivkovic, Linda Fabris, Peter M. Clark, Hui Ling, Masayoshi Shimizu, Roxana S. Redis, Maitri Y. Shah, Xinna Zhang, Yoshinaga OkugawaEun Jung Jung, Aristotelis Tsirigos, Li Huang, Jana Ferdin, Roberta Gafà, Riccardo Spizzo, Milena S. Nicoloso, Anurag N. Paranjape, Maryam Shariati, Aida Tiron, Jen Jen Yeh, Raul Teruel-Montoya, Lianchun Xiao, Sonia A. Melo, David Menter, Zhi Qin Jiang, Elsa R. Flores, Massimo Negrini, Ajay Goel, Menashe Bar-Eli, Sendurai A. Mani, Chang Gong Liu, Gabriel Lopez-Berestein, Ioana Berindan-Neagoe, Manel Esteller, Scott Kopetz, Giovanni Lanza, George A. Calin

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47 Citations (Scopus)

Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Article number98
JournalGenome biology
Volume18
Issue number1
DOIs
Publication statusPublished - 2017 May 24

Bibliographical note

Funding Information:
Dr. Calin is The Alan M. Gewirtz Leukemia and Lymphoma Society Scholar. This work was supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC). Work in Dr. Calin's laboratory is supported in part by the grant NIH/NCI 1 R01 CA182905-01, the UT MD Anderson Cancer Center SPORE in Melanoma grant from NCI (P50 CA093459), Aim at Melanoma Foundation and the Miriam and Jim Mulva research funds, the UT MD Anderson Cancer Center Brain SPORE (2P50CA127001), a Developmental Research award from Leukemia SPORE, a CLL Moonshot Flagship project, a 2015 Knowledge GAP MDACC grant, an Owens Foundation grant, and the Estate of C. G. Johnson Jr. Dr. Yeh's work was supported by the NIH/NCI (CA140424), Dr Elsa R. Flores by NCI R35CA197452, Dr Ioana Berindan-Neagoe by a Fulbright Senior Award Program 2014-2015, and Dr Martin Pichler by an Erwin-Schroedinger Scholarship of the Austrian Science Funds (project no. J3389-B23). Dr. Mani's laboratory is supported in part by the grant NIH/NCI 1 R01 CA155243. This work was supported also by a POC grant Nr.35/01.09.2016, ID 37_796, entitled Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance CANTEMIR. Dr. Rigoutsoswork was supported in part by a William M. Keck Foundation Medical Research Award, in part by institutional funds and in part by a grant (SAP#4100062221) from the Pennsylvania Department of Health which specifically disclaims responsibility for any analyses, interpretations, or conclusions. This research is supported in part by the National Institutes of Health through University of Texas MD Anderson Cancer Center Support Grant CA016672, as a portion of these studies were performed in the North and South Campus Flow Cytometry and Cellular Imaging Core (Principal Investigator: Ronald A. DePinho).

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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