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Gut. 2020 Jan 27. pii: gutjnl-2019-318903. doi: 10.1136/gutjnl-2019-318903. [Epub ahead of print]

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

Author information

1
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Division of Oncology, Medical University of Graz, Graz, Styria, Austria.
3
Center for RNA interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Gastroenterology Department, Kyungpook National University Hospital; School of Medicine, Kyungpook National University, Daegu, South Korea.
5
Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
6
Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
7
Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb, Croatia.
8
China-America Cancer Research Institute, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, China.
9
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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
Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
12
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
13
Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
14
Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
15
Department of Stem Cell Transplantation, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
16
Medical and Molecular Genetics Department, Indiana University, Indianapolis, Indiana, USA.
17
Department of Surgery, Dubrava Clinical Hospital, Zagreb, Croatia.
18
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Emilia-Romagna, Italy.
19
Mathematics in Medicine Program, The Houston Methodist Research Institute, Houston, Texas, USA.
20
Department of Medical Sciences, University of Ferrara, Ferrara, Emilia-Romagna, Italy.
21
Department of Molecular Diagnostics, Therapeutics and Translational Oncology, City of Hope National Medical Center, Duarte, California, USA.
22
Computational Medicine Center and Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
23
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA gcalin@mdanderson.org glopez@mdanderson.org.
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Contributed equally

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.

KEYWORDS:

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

PMID:
31988194
DOI:
10.1136/gutjnl-2019-318903

Conflict of interest statement

Competing interests: None declared.

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