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

J 2020

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

PICHLER, M., C. RODRIGUEZ-AGUAYO, SY NAM, M.P. DRAGOMIR, R. BAYRAKTAR et. al.

Basic information

Original name

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

Authors

PICHLER, M., C. RODRIGUEZ-AGUAYO, SY NAM, M.P. DRAGOMIR, R. BAYRAKTAR, S. ANFOSSI, E. KNUTSEN, C. IVAN, E. FUENTES-MATTEI, S.K. LEE, H. LING, T.C. IVKOVIC, G.L. HUANG, L. HUANG, Y. OKUGAWA, H. KATAYAMA, A. TAGUCHI, E. BAYRAKTAR, R. BHATTACHARYA, P. AMERO, W.R: HE, A.M. TRAN, Petra VYCHYTILOVÁ (203 Czech Republic, belonging to the institution), C. KLEC, D.L. BONILLA, X.N. ZHANG, S. KAPITANOVIC, B. LONCAR, R. GAFA, Z.H. WANG, V. CRISTINI, S.M. HANASH, M. BAR-ELI, G.N. LANZA, Ondřej SLABÝ (203 Czech Republic, guarantor, belonging to the institution), A. GOEL, I. RIGOUTSOS, G. LOPEZ-BERESTEIN and G.A. CALIN

Edition

Gut, LONDON, BMJ PUBLISHING GROUP, 2020, 0017-5749

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30219 Gastroenterology and hepatology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 23.059

RIV identification code

RIV/00216224:14740/20:00118365

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1136/gutjnl-2019-318903

UT WoS

000572338600017

Keywords in English

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

Abstract

V originále

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.

Citovat

PICHLER, M., C. RODRIGUEZ-AGUAYO, SY NAM, M.P. DRAGOMIR, R. BAYRAKTAR, S. ANFOSSI, E. KNUTSEN, C. IVAN, E. FUENTES-MATTEI, S.K. LEE, H. LING, T.C. IVKOVIC, G.L. HUANG, L. HUANG, Y. OKUGAWA, H. KATAYAMA, A. TAGUCHI, E. BAYRAKTAR, R. BHATTACHARYA, P. AMERO, W.R: HE, A.M. TRAN, Petra VYCHYTILOVÁ, C. KLEC, D.L. BONILLA, X.N. ZHANG, S. KAPITANOVIC, B. LONCAR, R. GAFA, Z.H. WANG, V. CRISTINI, S.M. HANASH, M. BAR-ELI, G.N. LANZA, Ondřej SLABÝ, A. GOEL, I. RIGOUTSOS, G. LOPEZ-BERESTEIN and G.A. CALIN. Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer. Gut. LONDON: BMJ PUBLISHING GROUP, 2020, vol. 69, No 10, p. 1818-1831. ISSN 0017-5749. Available from: https://dx.doi.org/10.1136/gutjnl-2019-318903.

@article{1751060,
   author = {Pichler, M. and RodriguezandAguayo, C. and Nam, SY and Dragomir, M.P. and Bayraktar, R. and Anfossi, S. and Knutsen, E. and Ivan, C. and FuentesandMattei, E. and Lee, S.K. and Ling, H. and Ivkovic, T.C. and Huang, G.L. and Huang, L. and Okugawa, Y. and Katayama, H. and Taguchi, A. and Bayraktar, E. and Bhattacharya, R. and Amero, P. and He, W.R: and Tran, A.M. and Vychytilová, Petra and Klec, C. and Bonilla, D.L. and Zhang, X.N. and Kapitanovic, S. and Loncar, B. and Gafa, R. and Wang, Z.H. and Cristini, V. and Hanash, S.M. and BarandEli, M. and Lanza, G.N. and Slabý, Ondřej and Goel, A. and Rigoutsos, I. and LopezandBerestein, G. and Calin, G.A.},
   article_location = {LONDON},
   article_number = {10},
   doi = {http://dx.doi.org/10.1136/gutjnl-2019-318903},
   keywords = {colorectal cancer; oncogenes; molecular genetics; gene therapy; angiogenesis},
   language = {eng},
   issn = {0017-5749},
   journal = {Gut},
   title = {Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer},
   url = {https://gut.bmj.com/content/69/10/1818},
   volume = {69},
   year = {2020}
}

TY  - JOUR
ID  - 1751060
AU  - Pichler, M. - Rodriguez-Aguayo, C. - Nam, SY - Dragomir, M.P. - Bayraktar, R. - Anfossi, S. - Knutsen, E. - Ivan, C. - Fuentes-Mattei, E. - Lee, S.K. - Ling, H. - Ivkovic, T.C. - Huang, G.L. - Huang, L. - Okugawa, Y. - Katayama, H. - Taguchi, A. - Bayraktar, E. - Bhattacharya, R. - Amero, P. - He, W.R: - Tran, A.M. - Vychytilová, Petra - Klec, C. - Bonilla, D.L. - Zhang, X.N. - Kapitanovic, S. - Loncar, B. - Gafa, R. - Wang, Z.H. - Cristini, V. - Hanash, S.M. - Bar-Eli, M. - Lanza, G.N. - Slabý, Ondřej - Goel, A. - Rigoutsos, I. - Lopez-Berestein, G. - Calin, G.A.
PY  - 2020
TI  - Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
JF  - Gut
VL  - 69
IS  - 10
SP  - 1818-1831
EP  - 1818-1831
PB  - BMJ PUBLISHING GROUP
SN  - 00175749
KW  - colorectal cancer
KW  - oncogenes
KW  - molecular genetics
KW  - gene therapy
KW  - angiogenesis
UR  - https://gut.bmj.com/content/69/10/1818
N2  - 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.
ER  -

PICHLER, M., C. RODRIGUEZ-AGUAYO, SY NAM, M.P. DRAGOMIR, R. BAYRAKTAR, S. ANFOSSI, E. KNUTSEN, C. IVAN, E. FUENTES-MATTEI, S.K. LEE, H. LING, T.C. IVKOVIC, G.L. HUANG, L. HUANG, Y. OKUGAWA, H. KATAYAMA, A. TAGUCHI, E. BAYRAKTAR, R. BHATTACHARYA, P. AMERO, W.R: HE, A.M. TRAN, Petra VYCHYTILOVÁ, C. KLEC, D.L. BONILLA, X.N. ZHANG, S. KAPITANOVIC, B. LONCAR, R. GAFA, Z.H. WANG, V. CRISTINI, S.M. HANASH, M. BAR-ELI, G.N. LANZA, Ondřej SLABÝ, A. GOEL, I. RIGOUTSOS, G. LOPEZ-BERESTEIN and G.A. CALIN. Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer. \textit{Gut}. LONDON: BMJ PUBLISHING GROUP, 2020, vol.~69, No~10, p.~1818-1831. ISSN~0017-5749. Available from: https://dx.doi.org/10.1136/gutjnl-2019-318903.

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