Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma

Kathleen M. Capaccione, Xuehui Hong, Katherine M. Morgan, Wenyu Liu, Michael J. Bishop, Lian Xin Liu, Elke Markert, Malik Deen, Christine Minerowicz, Thaddeus Allen, Sharon R. Pine

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelialmesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-β pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1-Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-β, Sox9 also acts downstream of NF-κB and Wnt/β-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.

Original languageEnglish (US)
Pages (from-to)3636-3650
Number of pages15
JournalOncotarget
Volume5
Issue number11
DOIs
StatePublished - 2014

All Science Journal Classification (ASJC) codes

  • Oncology

Keywords

  • EMT
  • Lung cancer
  • Notch1
  • Sox9
  • TGF-β

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  • Cite this

    Capaccione, K. M., Hong, X., Morgan, K. M., Liu, W., Bishop, M. J., Liu, L. X., Markert, E., Deen, M., Minerowicz, C., Allen, T., & Pine, S. R. (2014). Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma. Oncotarget, 5(11), 3636-3650. https://doi.org/10.18632/oncotarget.1970