Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer

Martin Pichler, Cristian Rodriguez-Aguayo, Su Youn Nam, Mihnea Paul Dragomir, Recep Bayraktar, Simone Anfossi, Erik Knutsen, Cristina Ivan, Enrique Fuentes-Mattei, Sang Kil Lee, Hui Ling, Tina Catela Ivkovic, Guoliang Huang, Li Huang, Yoshinaga Okugawa, Hiroyuki Katayama, Ayumu Taguchi, Emine Bayraktar, Rajat Bhattacharya, Paola AmeroWilliam Ruixian He, Anh M. Tran, Petra Vychytilova-Faltejskova, Christiane Klec, Diana L. Bonilla, Xinna Zhang, Sanja Kapitanovic, Bozo Loncar, Roberta Gafà, Zhihui Wang, Vittorio Cristini, Samir M. Hanash, Menashe Bar-Eli, Giovanni Lanza, Ondrej Slaby, Ajay Goel, Isidore Rigoutsos, Gabriel Lopez-Berestein, George Adrian Calin

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1818-1831
Number of pages14
JournalGut
Volume69
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • angiogenesis
  • colorectal cancer
  • gene therapy
  • molecular genetics
  • oncogenes

ASJC Scopus subject areas

  • Gastroenterology

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