MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer

Mick D. Edmonds, Kelli L. Boyd, Tamara Moyo, Ramkrishna Mitra, Robert Duszynski, Maria Pia Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Thomas Andl, Christine M. Eischen

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.

Original languageEnglish (US)
Pages (from-to)349-364
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number1
DOIs
StatePublished - Jan 4 2016

Fingerprint

MicroRNAs
Lung Neoplasms
Carcinogenesis
Lung
Regulator Genes
Adenoma
Transgenic Mice
Hyperplasia
Adenocarcinoma
Epithelial Cells
Gene Expression
Survival
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Edmonds, M. D., Boyd, K. L., Moyo, T., Mitra, R., Duszynski, R., Arrate, M. P., ... Eischen, C. M. (2016). MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. Journal of Clinical Investigation, 126(1), 349-364. https://doi.org/10.1172/JCI82720

MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. / Edmonds, Mick D.; Boyd, Kelli L.; Moyo, Tamara; Mitra, Ramkrishna; Duszynski, Robert; Arrate, Maria Pia; Chen, Xi; Zhao, Zhongming; Blackwell, Timothy S.; Andl, Thomas; Eischen, Christine M.

In: Journal of Clinical Investigation, Vol. 126, No. 1, 04.01.2016, p. 349-364.

Research output: Contribution to journalArticle

Edmonds, MD, Boyd, KL, Moyo, T, Mitra, R, Duszynski, R, Arrate, MP, Chen, X, Zhao, Z, Blackwell, TS, Andl, T & Eischen, CM 2016, 'MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer', Journal of Clinical Investigation, vol. 126, no. 1, pp. 349-364. https://doi.org/10.1172/JCI82720
Edmonds, Mick D. ; Boyd, Kelli L. ; Moyo, Tamara ; Mitra, Ramkrishna ; Duszynski, Robert ; Arrate, Maria Pia ; Chen, Xi ; Zhao, Zhongming ; Blackwell, Timothy S. ; Andl, Thomas ; Eischen, Christine M. / MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 1. pp. 349-364.
@article{f273908c45bd4cce8e19c124f526400f,
title = "MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer",
abstract = "MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.",
author = "Edmonds, {Mick D.} and Boyd, {Kelli L.} and Tamara Moyo and Ramkrishna Mitra and Robert Duszynski and Arrate, {Maria Pia} and Xi Chen and Zhongming Zhao and Blackwell, {Timothy S.} and Thomas Andl and Eischen, {Christine M.}",
year = "2016",
month = "1",
day = "4",
doi = "10.1172/JCI82720",
language = "English (US)",
volume = "126",
pages = "349--364",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer

AU - Edmonds, Mick D.

AU - Boyd, Kelli L.

AU - Moyo, Tamara

AU - Mitra, Ramkrishna

AU - Duszynski, Robert

AU - Arrate, Maria Pia

AU - Chen, Xi

AU - Zhao, Zhongming

AU - Blackwell, Timothy S.

AU - Andl, Thomas

AU - Eischen, Christine M.

PY - 2016/1/4

Y1 - 2016/1/4

N2 - MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.

AB - MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.

UR - http://www.scopus.com/inward/record.url?scp=84956638560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84956638560&partnerID=8YFLogxK

U2 - 10.1172/JCI82720

DO - 10.1172/JCI82720

M3 - Article

VL - 126

SP - 349

EP - 364

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -