Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma
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Kathleen M. Capaccione1,2, Xuehui Hong2,3, Katherine M. Morgan1,2, Wenyu Liu2, J. Michael Bishop4, LianXin Liu3, Elke Markert2,5, Malik Deen6, Christine Minerowicz6, Joseph R. Bertino5, Thaddeus Allen4, and Sharon R. Pine1,2,5
1 Department of Pharmacology, Rutgers Graduate School of Biomedical Science, Piscataway, New Jersey
2 Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
3 Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
4 G.W. Hooper Research Foundation, University of California, San Francisco, CA
5 Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, New Jersey
6 Department of Pathology, Robert Wood Johnson Medical School, New Brunswick, New Jersey
Sharon R. Pine, email:
Keywords: Sox9, Notch1, TGF-β, lung cancer, EMT
Received: May 01, 2014 Accepted: May 19, 2014 Published: May 19, 2014
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 epithelial-mesenchymal 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, BMP, EGFR, 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.
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