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Original research
Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
  1. Martin Pichler1,2,
  2. Cristian Rodriguez-Aguayo1,3,
  3. Su Youn Nam1,4,
  4. Mihnea Paul Dragomir1,
  5. Recep Bayraktar1,
  6. Simone Anfossi1,
  7. Erik Knutsen1,5,
  8. Cristina Ivan1,3,
  9. Enrique Fuentes-Mattei1,
  10. Sang Kil Lee1,6,
  11. Hui Ling1,
  12. Tina Catela Ivkovic1,7,
  13. Guoliang Huang1,8,
  14. Li Huang9,
  15. Yoshinaga Okugawa10,
  16. Hiroyuki Katayama11,
  17. Ayumu Taguchi11,
  18. Emine Bayraktar1,
  19. Rajat Bhattacharya12,
  20. Paola Amero1,
  21. William Ruixian He1,
  22. Anh M Tran1,
  23. Petra Vychytilova-Faltejskova13,14,
  24. Christiane Klec2,
  25. Diana L Bonilla15,
  26. Xinna Zhang3,16,
  27. Sanja Kapitanovic7,
  28. Bozo Loncar17,
  29. Roberta Gafà18,
  30. Zhihui Wang19,
  31. Vittorio Cristini19,
  32. Samir M Hanash11,
  33. Menashe Bar-Eli9,
  34. Giovanni Lanza20,
  35. Ondrej Slaby13,14,
  36. Ajay Goel10,21,
  37. Isidore Rigoutsos22,
  38. Gabriel Lopez-Berestein1,3,
  39. George Adrian Calin1,3
  1. 1 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2 Division of Oncology, Medical University of Graz, Graz, Styria, Austria
  3. 3 Center for RNA interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  4. 4 Gastroenterology Department, Kyungpook National University Hospital; School of Medicine, Kyungpook National University, Daegu, South Korea
  5. 5 Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway
  6. 6 Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
  7. 7 Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia
  8. 8 China-America Cancer Research Institute, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, China
  9. 9 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  10. 10 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
  11. 11 Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  12. 12 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  13. 13 Central European Institute of Technology, Masaryk University, Brno, Czech Republic
  14. 14 Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  15. 15 Department of Stem Cell Transplantation, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  16. 16 Medical and Molecular Genetics Department, Indiana University, Indianapolis, Indiana, USA
  17. 17 Department of Surgery, Dubrava Clinical Hospital, Zagreb, Croatia
  18. 18 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Emilia-Romagna, Italy
  19. 19 Mathematics in Medicine Program, The Houston Methodist Research Institute, Houston, Texas, USA
  20. 20 Department of Medical Sciences, University of Ferrara, Ferrara, Emilia-Romagna, Italy
  21. 21 Department of Molecular Diagnostics, Therapeutics and Translational Oncology, City of Hope National Medical Center, Duarte, California, USA
  22. 22 Computational Medicine Center and Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr George Adrian Calin, Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; gcalin{at}mdanderson.org; Dr Gabriel Lopez-Berestein, Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; glopez{at}mdanderson.org

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.

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

  • MP, CR-A, SYN and MPD contributed equally.

  • Correction notice This article has been corrected since it published Online First. The funding statement has been updated.

  • Contributors Conception and design: MP, CR-A, SYN, MPD, GAC. Development of methodology: MP, CR-A, SYN, MPD, GAC. Acquisition of data (provided animals, acquired and treated patients, provided facilities, etc): MP, CR-A, SYN, MPD, RBa, SA, EK, EF-M, SKL, HL, GH, TCI, LH, YO, HK, AT, EB, RBh, PA, WRH, AMT, PV, DLB, XZ, CI, SK, BL, RG, ZW, SMH, MBE, GL, OS, AG, IR. Analysis and interpretation of data (eg, statistical analysis, biostatistics, computational analysis, mathematical analysis): MP, SYN, MPD, CI, ZW, VC, IR, GAC. Writing, review and/or revision of the manuscript: MP, CR-A, SYN, PA, SA, EK, MPD, IR, GAC. Administrative, technical or material support (ie, reporting or organising data, constructing databases): MP, CR-A, SYN, PA, SA, EK, MPD, GAC. Study supervision: GL-B, GAC.

  • Funding GAC is the Felix L. Endowed Professor in Basic Science. Work in GAC’s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1, an NIGMS 1R01GM122775-01 grant, a U54 grant #CA096297/CA096300 – UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Ladies Leukemia League grant, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a Sister Institution Network Fund (SINF) 2017 grant and the Estate of C. G. Johnson Jr. GH was supported by China scholarship Council. CR-A was supported by the NIH through the Ovarian SPORE Career Enhancement Program, the NCI grants FP00000019. MP was supported by an Erwin Schroedinger Scholarship of the Austrian Science Funds (No. J3389-B23). ZW and VC were supported from the National Science Foundation Grant DMS-1930583, the NIH Grants 1U01CA196403, 1U01CA213759, 1R01CA226537, 1R01CA222007 and U54CA210181. GL-B is the John Q. Gaines Professor of Cancer Research. AG’s work was supported by the grants CA72851, CA181572, CA184792 and CA187956 from the National Cancer Institute, National Institute of Health. IR is the Richard Hevner Professor in Computational Medicine at Thomas Jefferson University. IR’s work was partially supported by a William M. Keck Foundation grant and by Institutional Funds. The Functional Proteomics RPPA Core facility and the Flow Cytometry and Cellular Imaging Core Facility (FCCICF) are supported by NCI Cancer Center Support Grant P30CA16672. AMT was supported by the CPRIT Research Training Program (RP170067).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Institutional Review Board of UT MDACC Texas LAB07-0734; Ethics Committee of University of Ferrara, Italy; Ethics Committee of Mie University Graduate School of Medicine, Japan; Ethics Committee of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Czech Republic Ethics Committee of Croatian Human Tumor Bank.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open-access repository. (i) Genome-wide microarray expression profiling to study the genetic landscape alterations induced by the knock-down of FLANC by shRNA/overexpression of FLANC in HCT-116 cells. (ii) Gene expression omnibus. (iii) Data are publicly available starting with 27 December 2019. As per your request, we have released the data for public access: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE127785; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE127786.

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