Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
Authors: Recep Bayraktar
Vittorio Cristini
Guoliang Huang
Li Huang
Diana L Bonilla
Petra Vychytilova-Faltejskova
Yoshinaga Okugawa
Su Youn Nam
Xinna Zhang
Hui Ling
Menashe Bar-Eli
Samir M Hanash
William Ruixian He
Roberta Gaf√†
Hiroyuki Katayama
Emine Bayraktar
Sang Kil Lee
Erik Knutsen
Zhihui Wang
Cristian Rodriguez-Aguayo
Isidore Rigoutsos
Ondrej Slaby
George Adrian Calin
Cristina Ivan
Paola Amero
Gabriel Lopez-Berestein
Enrique Fuentes-Mattei
Tina Catela Ivkovic
Bozo Loncar
Simone Anfossi
Anh M Tran
Martin Pichler
Rajat Bhattacharya
Mihnea Paul Dragomir
Giovanni Lanza
Ayumu Taguchi
Ajay Goel
Sanja Kapitanovic
Christiane Klec
Journal: Gut (2020)
Discipline: CLINICAL MEDICINE
Keywords: angiogenesis; colorectal cancer; gene therapy; molecular genetics; oncogenes.
Affiliations: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Division of Oncology, Medical University of Graz, Graz, Styria, Austria., Center for RNA interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Gastroenterology Department, Kyungpook National University Hospital; School of Medicine, Kyungpook National University, Daegu, South Korea., Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Troms√∏, Norway., Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea., Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia., China-America Cancer Research Institute, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, China., Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Center for Gastrointestinal Research and Center for Translational Genomics and Oncology, Baylor Scott and White Health Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA., Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic., Department of Stem Cell Transplantation, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Medical and Molecular Genetics Department, Indiana University, Indianapolis, Indiana, USA., Department of Surgery, Dubrava Clinical Hospital, Zagreb, Croatia., Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Emilia-Romagna, Italy., Mathematics in Medicine Program, The Houston Methodist Research Institute, Houston, Texas, USA., Department of Medical Sciences, University of Ferrara, Ferrara, Emilia-Romagna, Italy., Department of Molecular Diagnostics, Therapeutics and Translational Oncology, City of Hope National Medical Center, Duarte, California, USA., Computational Medicine Center and Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA  .

Abstract:  Objective: To investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target. Design: FLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases. Results: FLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis. Conclusions: Based on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients. 

Retracted: No

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