Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy

Elvira L. Liclican, Tonya C. Walser, Saswati Hazra, Kostyantyn Krysan, Stacy J. Park, Paul C. Pagano, Brian K. Gardner, Jill E. Larsen, John D. Minna, Steven M. Dubinett

Research output: Contribution to journalArticle

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Abstract

Understanding the molecular pathogenesis of lung cancer is necessary to identify biomarkers/targets specific to individual airway molecular profiles and to identify options for targeted chemoprevention. Herein, we identify mechanisms by which loss of microRNA (miRNA)125a-3p (miR125a) contributes to the malignant potential of human bronchial epithelial cells (HBEC) harboring an activating point mutation of the K-ras proto-oncogene (HBEC K-ras). Among other miRNAs, we identified significant miR125a loss in HBEC K-ras lines and determined that miR125a is regulated by the PEA3 transcription factor. PEA3 is upregulated in HBEC K-ras cells, and genetic knockdown of PEA3 restores miR125a expression. From a panel of inflammatory/angiogenic factors, we identified increased CXCL1 and vascular endothelial growth factor (VEGF) production by HBEC K-ras cells and determined that miR125a overexpression significantly reduces K-ras-mediated production of these tumorigenic factors. miR125a overexpression also abrogates increased proliferation of HBEC K-ras cells and suppresses anchorage-independent growth (AIG) of HBEC K-ras/P53 cells, the latter of which is CXCL1-dependent. Finally, pioglitazone increases levels of miR125a in HBEC K-ras cells via PEA3 downregulation. In addition, pioglitazone and miR125a overexpression elicit similar phenotypic responses, including suppression of both proliferation and VEGF production. Our findings implicate miR125a loss in lung carcinogenesis and lay the groundwork for future studies to determine whether miR125a is a possible biomarker for lung carcinogenesis and/or a chemoprevention target. Moreover, our studies illustrate that pharmacologic augmentation of miR125a in K-ras-mutated pulmonary epithelium effectively abrogates several deleterious downstream events associated with the mutation.

Original languageEnglish (US)
Pages (from-to)845-855
Number of pages11
JournalCancer Prevention Research
Volume7
Issue number8
DOIs
StatePublished - 2014

Fingerprint

MicroRNAs
Lung
Epithelial Cells
pioglitazone
Chemoprevention
Carcinogenesis
Biomarkers
ras Genes
Proto-Oncogenes
Angiogenesis Inducing Agents
Point Mutation
Vascular Endothelial Growth Factor A
Lung Neoplasms
Down-Regulation
Epithelium
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Liclican, E. L., Walser, T. C., Hazra, S., Krysan, K., Park, S. J., Pagano, P. C., ... Dubinett, S. M. (2014). Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy. Cancer Prevention Research, 7(8), 845-855. https://doi.org/10.1158/1940-6207.CAPR-14-0063

Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy. / Liclican, Elvira L.; Walser, Tonya C.; Hazra, Saswati; Krysan, Kostyantyn; Park, Stacy J.; Pagano, Paul C.; Gardner, Brian K.; Larsen, Jill E.; Minna, John D.; Dubinett, Steven M.

In: Cancer Prevention Research, Vol. 7, No. 8, 2014, p. 845-855.

Research output: Contribution to journalArticle

Liclican, EL, Walser, TC, Hazra, S, Krysan, K, Park, SJ, Pagano, PC, Gardner, BK, Larsen, JE, Minna, JD & Dubinett, SM 2014, 'Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy', Cancer Prevention Research, vol. 7, no. 8, pp. 845-855. https://doi.org/10.1158/1940-6207.CAPR-14-0063
Liclican, Elvira L. ; Walser, Tonya C. ; Hazra, Saswati ; Krysan, Kostyantyn ; Park, Stacy J. ; Pagano, Paul C. ; Gardner, Brian K. ; Larsen, Jill E. ; Minna, John D. ; Dubinett, Steven M. / Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy. In: Cancer Prevention Research. 2014 ; Vol. 7, No. 8. pp. 845-855.
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AU - Park, Stacy J.

AU - Pagano, Paul C.

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AB - Understanding the molecular pathogenesis of lung cancer is necessary to identify biomarkers/targets specific to individual airway molecular profiles and to identify options for targeted chemoprevention. Herein, we identify mechanisms by which loss of microRNA (miRNA)125a-3p (miR125a) contributes to the malignant potential of human bronchial epithelial cells (HBEC) harboring an activating point mutation of the K-ras proto-oncogene (HBEC K-ras). Among other miRNAs, we identified significant miR125a loss in HBEC K-ras lines and determined that miR125a is regulated by the PEA3 transcription factor. PEA3 is upregulated in HBEC K-ras cells, and genetic knockdown of PEA3 restores miR125a expression. From a panel of inflammatory/angiogenic factors, we identified increased CXCL1 and vascular endothelial growth factor (VEGF) production by HBEC K-ras cells and determined that miR125a overexpression significantly reduces K-ras-mediated production of these tumorigenic factors. miR125a overexpression also abrogates increased proliferation of HBEC K-ras cells and suppresses anchorage-independent growth (AIG) of HBEC K-ras/P53 cells, the latter of which is CXCL1-dependent. Finally, pioglitazone increases levels of miR125a in HBEC K-ras cells via PEA3 downregulation. In addition, pioglitazone and miR125a overexpression elicit similar phenotypic responses, including suppression of both proliferation and VEGF production. Our findings implicate miR125a loss in lung carcinogenesis and lay the groundwork for future studies to determine whether miR125a is a possible biomarker for lung carcinogenesis and/or a chemoprevention target. Moreover, our studies illustrate that pharmacologic augmentation of miR125a in K-ras-mutated pulmonary epithelium effectively abrogates several deleterious downstream events associated with the mutation.

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