期刊
GUT
卷 69, 期 10, 页码 1818-1831出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2019-318903
关键词
colorectal cancer; oncogenes; molecular genetics; gene therapy; angiogenesis
资金
- National Institutes of Health (NIH/NCATS) grant through the NIH Common Fund, Office of Strategic Coordination (OSC) [UH3TR00943-01]
- NCI [FP00000019, 1R01 CA182905-01, 1R01CA222007-01A1]
- NIGMS [1R01GM122775-01]
- U54 grant - UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project [CA096297/CA096300]
- DOD [CA160445P1]
- Ladies Leukemia League grant
- Chronic Lymphocytic Leukemia Moonshot Flagship project
- Sister Institution Network Fund (SINF) 2017 grant
- Estate of C. G.
- China scholarship Council
- NIH through the Ovarian SPORE Career Enhancement Program
- Erwin Schroedinger Scholarship of the Austrian Science Funds [J3389-B23]
- National Science Foundation Grant [DMS-1930583]
- NIH [1U01CA196403, 1U01CA213759, 1R01CA226537, 1R01CA222007, U54CA210181]
- National Cancer Institute, National Institute of Health [CA72851, CA181572, CA184792, CA187956]
- William M. Keck Foundation grant
- NCI Cancer Center Support Grant [P30CA16672]
- CPRIT Research Training Program [RP170067]
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.
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