Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma

Daiana D. Becker-Santos; Kelsie L. Thu; John C. English; Larissa A. Pikor; Victor D. Martinez; May Zhang; Emily A. Vucic; Margaret T.Y. Luk; Anita Carraro; Jagoda Korbelik; Daniela Piga; Nicolas M. Lhomme; Mike J. Tsay; John Yee; Calum E. MacAulay; Stephen Lam; William W. Lockwood; Wendy P. Robinson; Igor Jurisica; Wan L. Lam

doi:10.1002/path.4765

Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma

Daiana D. Becker-Santos, Kelsie L. Thu, John C. English, Larissa A. Pikor, Victor D. Martinez, May Zhang, Emily A. Vucic, Margaret T.Y. Luk, Anita Carraro, Jagoda Korbelik, Daniela Piga, Nicolas M. Lhomme, Mike J. Tsay, John Yee, Calum E. MacAulay, Stephen Lam, William W. Lockwood, Wendy P. Robinson, Igor Jurisica, Wan L. Lam

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

39 Citas (Scopus)

Resumen

Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these ‘oncofetal’ miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40–70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients.

Idioma original	English
Páginas (desde-hasta)	161-172
Número de páginas	12
Publicación	Journal of Pathology
Volumen	240
N.º	2
DOI	https://doi.org/10.1002/path.4765
Estado	Published - oct. 1 2016
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
We would like to thank Kim Lonergan and Heather Saprunoff for analytical and technical assistance, The Cancer Genome Atlas Research Network for access to miRNA- and RNA-sequencing data used for validation, and KM Plotter for gene expression data used for survival analysis. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (FDN-143345), and the Canadian Cancer Society. Computational analysis was supported in part by the Ontario Research Fund (GL2-01-030), the Canada Foundation for Innovation (CFI #12301, #203373, #29272, #225404, and #30865), and a Canada Research Chair Program (CRC #203373 and #225404) to IJ. DDBS, KLT, and LAP were supported by Vanier Canada Graduate Scholarships. WWL is a Michael Smith Foundation for Health Research Scholar.

Publisher Copyright:
Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ASJC Scopus Subject Areas

Pathology and Forensic Medicine

ODS de las Naciones Unidas

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Becker-Santos, D. D., Thu, K. L., English, J. C., Pikor, L. A., Martinez, V. D., Zhang, M., Vucic, E. A., Luk, M. T. Y., Carraro, A., Korbelik, J., Piga, D., Lhomme, N. M., Tsay, M. J., Yee, J., MacAulay, C. E., Lam, S., Lockwood, W. W., Robinson, W. P., Jurisica, I., & Lam, W. L. (2016). Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma. Journal of Pathology, 240(2), 161-172. https://doi.org/10.1002/path.4765

Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma. / Becker-Santos, Daiana D.; Thu, Kelsie L.; English, John C. et al.
En: Journal of Pathology, Vol. 240, N.º 2, 01.10.2016, p. 161-172.

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

Becker-Santos, DD, Thu, KL, English, JC, Pikor, LA, Martinez, VD, Zhang, M, Vucic, EA, Luk, MTY, Carraro, A, Korbelik, J, Piga, D, Lhomme, NM, Tsay, MJ, Yee, J, MacAulay, CE, Lam, S, Lockwood, WW, Robinson, WP, Jurisica, I & Lam, WL 2016, 'Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma', Journal of Pathology, vol. 240, n.º 2, pp. 161-172. https://doi.org/10.1002/path.4765

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title = "Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma",

abstract = "Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these {\textquoteleft}oncofetal{\textquoteright} miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40–70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients.",

author = "Becker-Santos, {Daiana D.} and Thu, {Kelsie L.} and English, {John C.} and Pikor, {Larissa A.} and Martinez, {Victor D.} and May Zhang and Vucic, {Emily A.} and Luk, {Margaret T.Y.} and Anita Carraro and Jagoda Korbelik and Daniela Piga and Lhomme, {Nicolas M.} and Tsay, {Mike J.} and John Yee and MacAulay, {Calum E.} and Stephen Lam and Lockwood, {William W.} and Robinson, {Wendy P.} and Igor Jurisica and Lam, {Wan L.}",

note = "Funding Information: We would like to thank Kim Lonergan and Heather Saprunoff for analytical and technical assistance, The Cancer Genome Atlas Research Network for access to miRNA- and RNA-sequencing data used for validation, and KM Plotter for gene expression data used for survival analysis. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (FDN-143345), and the Canadian Cancer Society. Computational analysis was supported in part by the Ontario Research Fund (GL2-01-030), the Canada Foundation for Innovation (CFI #12301, #203373, #29272, #225404, and #30865), and a Canada Research Chair Program (CRC #203373 and #225404) to IJ. DDBS, KLT, and LAP were supported by Vanier Canada Graduate Scholarships. WWL is a Michael Smith Foundation for Health Research Scholar. Publisher Copyright: Copyright {\textcopyright} 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

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AU - Becker-Santos, Daiana D.

AU - Thu, Kelsie L.

AU - English, John C.

AU - Pikor, Larissa A.

AU - Martinez, Victor D.

AU - Zhang, May

AU - Vucic, Emily A.

AU - Luk, Margaret T.Y.

AU - Carraro, Anita

AU - Korbelik, Jagoda

AU - Piga, Daniela

AU - Lhomme, Nicolas M.

AU - Tsay, Mike J.

AU - Yee, John

AU - MacAulay, Calum E.

AU - Lam, Stephen

AU - Lockwood, William W.

AU - Robinson, Wendy P.

AU - Jurisica, Igor

AU - Lam, Wan L.

N1 - Funding Information: We would like to thank Kim Lonergan and Heather Saprunoff for analytical and technical assistance, The Cancer Genome Atlas Research Network for access to miRNA- and RNA-sequencing data used for validation, and KM Plotter for gene expression data used for survival analysis. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (FDN-143345), and the Canadian Cancer Society. Computational analysis was supported in part by the Ontario Research Fund (GL2-01-030), the Canada Foundation for Innovation (CFI #12301, #203373, #29272, #225404, and #30865), and a Canada Research Chair Program (CRC #203373 and #225404) to IJ. DDBS, KLT, and LAP were supported by Vanier Canada Graduate Scholarships. WWL is a Michael Smith Foundation for Health Research Scholar. Publisher Copyright: Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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N2 - Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these ‘oncofetal’ miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40–70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients.

AB - Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these ‘oncofetal’ miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40–70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients.

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Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

ODS de las Naciones Unidas

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