Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
| Autor: | Mihnea P. Dragomir, Menashe Bar-Eli, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Ayumu Taguchi, Tina Catela Ivkovic, Diana L. Bonilla, Zhihui Wang, Xinna Zhang, Isidore Rigoutsos, Giovanni Lanza, Erik Knutsen, Hiroyuki Katayama, Cristina Ivan, Sanja Kapitanović, Emine Bayraktar, Martin Pichler, Anh M. Tran, Li Huang, Recep Bayraktar, Rajat Bhattacharya, Ondrej Slaby, Yoshinaga Okugawa, Bozo Loncar, George A. Calin, Simone Anfossi, Ajay Goel, Paola Amero, William Ruixian He, Samir M. Hanash, Sang Kil Lee, Guoliang Huang, Roberta Gafà, Su Youn Nam, Gabriel Lopez-Berestein, Vittorio Cristini, Hui Ling, Christiane Klec, Petra Vychytilova-Faltejskova |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetic Markers STAT3 Transcription Factor Vascular Endothelial Growth Factor A Small interfering RNA Colorectal cancer Angiogenesis Carcinogenesis oncogenes Genetic enhancement colorectal cancer Biology Article NO angiogenesis gene therapy molecular genetics 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Drug Discovery medicine Biomarkers Tumor Animals Humans Cell Proliferation Neovascularization Pathologic Gastroenterology Genetic Therapy medicine.disease Long non-coding RNA 3. Good health Pharmacogenomic Testing Gene Expression Regulation Neoplastic Vascular endothelial growth factor A 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research RNA Long Noncoding Colorectal Neoplasms angiogenesis colorectal cancer gene therapy molecular genetics oncogenes |
| Zdroj: | Gut |
| Popis: | ObjectiveTo 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.DesignFLANC 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.ResultsFLANC, 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.ConclusionsBased 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. |
| Databáze: | OpenAIRE |
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