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 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.
Highlights
Sox9 is a member of the high-mobility group-box class DNA-binding protein family of transcription factors and plays a critical role in embryonic development, cell fate determination and lineage commitment
We show that the Notch1-Sox9 signaling axis is evolutionarily conserved through a novel RBP-Jκ binding site at -10 bp relative to the SOX9 promoter and that Sox9 expression is regulated by Notch1 in lung ADC independent of TGF-β signaling
We further investigated Sox9 expression at the protein level in 50 human lung ADC surgical samples and paired normal adjacent tissue (NAT)
Summary
Sox is a member of the high-mobility group-box class DNA-binding protein family of transcription factors and plays a critical role in embryonic development, cell fate determination and lineage commitment. Sox orchestrates chondrogenesis, bone formation and testis development [1,2]. Germline SOX9 mutations cause campomelic dysplasia, a disorder characterized by numerous skeletal abnormalities and XY sex reversal [3]. Infants with mutant SOX9 usually die due to respiratory distress shortly after birth [4]. This clinical finding likely reflects the role of Sox in the developing lung. Sox is required for branching morphogenesis in the lungs and for controlling alveolar epithelial progenitor cell proliferation [5,6]
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