MiR-215-5p is a tumor suppressor in colorectal cancer targeting
EGFR ligand epiregulin and its transcriptional inducer HOXB9

J 2017

MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9

VYCHYTILOVÁ, Petra, Jana MERHAUTOVÁ, Táňa MACHÁČKOVÁ, Irene GUTIERREZ-GARCIA, José GARCIA-SOLANO et. al.

Basic information

Original name

MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9

Authors

VYCHYTILOVÁ, Petra (203 Czech Republic, belonging to the institution), Jana MERHAUTOVÁ (203 Czech Republic, belonging to the institution), Táňa MACHÁČKOVÁ (203 Czech Republic, belonging to the institution), Irene GUTIERREZ-GARCIA (724 Spain), José GARCIA-SOLANO (724 Spain), Lenka RADOVÁ (203 Czech Republic, belonging to the institution), Dominika BRCHNELOVÁ (703 Slovakia, belonging to the institution), Kateřina SLABÁ (203 Czech Republic, belonging to the institution), Marek SVOBODA (203 Czech Republic, belonging to the institution), Jana HALÁMKOVÁ (203 Czech Republic, belonging to the institution), Regina DEMLOVÁ (203 Czech Republic, belonging to the institution), Igor KISS (203 Czech Republic, belonging to the institution), Rostislav VYZULA (203 Czech Republic, belonging to the institution), Pablo CONESA-ZAMORA (724 Spain) and Ondřej SLABÝ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Oncogenesis, New York, USA, Nature publishing group, 2017, 2157-9024

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30200 3.2 Clinical medicine

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.722

RIV identification code

RIV/00216224:14740/17:00095449

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1038/s41389-017-0006-6

UT WoS

000423913000003

Keywords (in Czech)

miR-215; kolorektální karcinom; EGFR; proliferace; nádorový supresor; HOXB9; epiregulin

Keywords in English

miR-215; colorectal cancer; EGFR; proliferation; tumor suppressor; HOXB9; epiregulin

Abstract

V originále

Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.

Links

GA16-18257S, research and development project

Name: Studium mechanizmu spojeného s nádorově supresorovou funkcí miR-215 a substituce této miRNA jako nové lečebné strategie u kolorektálního karcinomu

Investor: Czech Science Foundation

LM2015090, research and development project

Name: Český národní uzel Evropské sítě infrastruktur klinického výzkumu (Acronym: CZECRIN)

Investor: Ministry of Education, Youth and Sports of the CR

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1284/2015, interní kód MU

Name: Experimentální farmakologický vývoj v neuropsychiatrii a onkologii

Investor: Masaryk University, Category A

MUNI/11/InGA09/2014, interní kód MU

Name: Studium terapeuticky využitelných vlastností mikroRNA-215 v animálním modelu kolorektálního karcinomu (Acronym: miR-215 kolorektální karcinom)

Investor: Masaryk University

Citovat

VYCHYTILOVÁ, Petra, Jana MERHAUTOVÁ, Táňa MACHÁČKOVÁ, Irene GUTIERREZ-GARCIA, José GARCIA-SOLANO, Lenka RADOVÁ, Dominika BRCHNELOVÁ, Kateřina SLABÁ, Marek SVOBODA, Jana HALÁMKOVÁ, Regina DEMLOVÁ, Igor KISS, Rostislav VYZULA, Pablo CONESA-ZAMORA and Ondřej SLABÝ. MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9. Oncogenesis. New York, USA: Nature publishing group, 2017, vol. 6, No 11, p. 399-412. ISSN 2157-9024. Available from: https://dx.doi.org/10.1038/s41389-017-0006-6.

@article{1405392,
   author = {Vychytilová, Petra and Merhautová, Jana and Macháčková, Táňa and GutierrezandGarcia, Irene and GarciaandSolano, José and Radová, Lenka and Brchnelová, Dominika and Slabá, Kateřina and Svoboda, Marek and Halámková, Jana and Demlová, Regina and Kiss, Igor and Vyzula, Rostislav and ConesaandZamora, Pablo and Slabý, Ondřej},
   article_location = {New York, USA},
   article_number = {11},
   doi = {http://dx.doi.org/10.1038/s41389-017-0006-6},
   keywords = {miR-215; colorectal cancer; EGFR; proliferation; tumor suppressor; HOXB9; epiregulin},
   language = {eng},
   issn = {2157-9024},
   journal = {Oncogenesis},
   title = {MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9},
   url = {https://www.nature.com/articles/s41389-017-0006-6},
   volume = {6},
   year = {2017}
}

TY  - JOUR
ID  - 1405392
AU  - Vychytilová, Petra - Merhautová, Jana - Macháčková, Táňa - Gutierrez-Garcia, Irene - Garcia-Solano, José - Radová, Lenka - Brchnelová, Dominika - Slabá, Kateřina - Svoboda, Marek - Halámková, Jana - Demlová, Regina - Kiss, Igor - Vyzula, Rostislav - Conesa-Zamora, Pablo - Slabý, Ondřej
PY  - 2017
TI  - MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9
JF  - Oncogenesis
VL  - 6
IS  - 11
SP  - 399-412
EP  - 399-412
PB  - Nature publishing group
SN  - 21579024
KW  - miR-215
KW  - colorectal cancer
KW  - EGFR
KW  - proliferation
KW  - tumor suppressor
KW  - HOXB9
KW  - epiregulin
UR  - https://www.nature.com/articles/s41389-017-0006-6
L2  - https://www.nature.com/articles/s41389-017-0006-6
N2  - Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.
ER  -

VYCHYTILOVÁ, Petra, Jana MERHAUTOVÁ, Táňa MACHÁČKOVÁ, Irene GUTIERREZ-GARCIA, José GARCIA-SOLANO, Lenka RADOVÁ, Dominika BRCHNELOVÁ, Kateřina SLABÁ, Marek SVOBODA, Jana HALÁMKOVÁ, Regina DEMLOVÁ, Igor KISS, Rostislav VYZULA, Pablo CONESA-ZAMORA and Ondřej SLABÝ. MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9. \textit{Oncogenesis}. New York, USA: Nature publishing group, 2017, vol.~6, No~11, p.~399-412. ISSN~2157-9024. Available from: https://dx.doi.org/10.1038/s41389-017-0006-6.

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