Sox2 is important for two crucial processes in lung development: Branching morphogenesis and epithelial cell differentiation

Abstract

The primary lung bud originates from the foregut and develops into the bronchial tree by repetitive branching and outgrowing of the airway. The Sry related HMG box protein Sox2 is expressed in a cyclic manner during initiation and branching morphogenesis of the lung. It is highly expressed in non-branching regions and absent from branching regions, suggesting that downregulation of Sox2 is mandatory for airway epithelium to respond to branch inducing signals. Therefore, we developed transgenic mice that express a doxycycline inducible Sox2 in the airway epithelium. Continuous expression of Sox2 hampers the branching process resulting in a severe reduction of the number of airways. In addition, the bronchioli transiently go over into enlarged, alveolar-like airspaces, a pathology described as bronchiolization of alveoli. Furthermore, a substantial increase was observed of cGRP positive neuroendocrine cells and Delta Np63 isoform expressing (pre-) basal cells, which are both committed precursor-like cells. Thus, Sox2 prevents airways from branching and prematurely drives cells into committed progenitors, apparently rendering these committed progenitors unresponsive to branch inducing signals. However, Sox2 overexpression does not lead to a complete abrogation of the epithelial differentiation program.

SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer

“…In support of this, SOX2 proved to be significantly co-expressed with typical markers of squamous cell carcinoma differentiation, such as p63. 9,15,25 Besides the lung, SOX2 has been found to be amplified and expressed in squamous cell carcinomas originating from other organ sites, predominantly derived from the embryonic foregut. 9,21,22 Recently, we found SOX2 to be amplified and expressed in squamous cell carcinomas originating from non-foregut tissues, such as the skin, the cervix, and the penis, 23 indicating that SOX2 might be a general marker for squamous cell carcinoma differentiation regardless the tissue of origin.…”

“…High SOX2 expression is found in all endoderm cells of the undivided foregut with protein levels being higher in the dorsal foregut (the future esophagus) and lower in the ventral foregut (the future trachea). 15,16 During bronchogenesis in the developing lung, SOX2 is precisely regulated and forced overexpression of SOX2 leads to a block of airway branching. 15 In the adult, SOX2 expression is found in the basal cell layer of the esophagus and in bronchial epithelial cells of the lung, whereas it is absent in alveolar cells.…”

“…15,16 During bronchogenesis in the developing lung, SOX2 is precisely regulated and forced overexpression of SOX2 leads to a block of airway branching. 15 In the adult, SOX2 expression is found in the basal cell layer of the esophagus and in bronchial epithelial cells of the lung, whereas it is absent in alveolar cells. 17 In lung cancer, SOX2 amplification and expression can be found in a large subset of squamous cell carcinomas.…”

Expression of MET and SOX2 genes in non-small cell lung carcinoma with EGFR mutation

“…SOX2 is also expressed in the developing respiratory epithelium and is restricted to conducting airways of the mature lung (19). SOX2 is induced in the bronchiolar epithelium during repair after toxicant-induced injury (20).…”

“…SOX2 is induced in the bronchiolar epithelium during repair after toxicant-induced injury (20). Overexpression of SOX2 in lung epithelium during early development disrupted branching morphogenesis, causing cystic lungs and neonatal death (19). It has been suggested that SOX2, which belongs to group B of the SOX family plays critical roles in cell fate determination, differentiation and proliferation (21,22).…”