Sox2 Cooperates with Inflammation-Mediated Stat3 Activation in the Malignant Transformation of Foregut Basal Progenitor Cells

Abstract

Summary Sox2 regulates the self-renewal of multiple types of stem cells. Recent studies suggest it also plays oncogenic roles in the formation of squamous carcinoma in several organs, including the esophagus where Sox2 is predominantly expressed in the basal progenitor cells of the stratified epithelium. Here, we use mouse genetic models to reveal a novel mechanism by which Sox2 cooperates with microenvironmental signals to malignantly transform epithelial progenitor cells. Conditional overexpression of Sox2 in basal cells expands the progenitor population in both the esophagus and forestomach. Significantly, carcinoma only develops in the forestomach where pathological progression correlates with inflammation and nuclear localization of Stat3 in progenitor cells. Importantly, co-overexpression of Sox2 and activated Stat3 (Stat3C) also transforms esophageal basal cells but not the differentiated suprabasal cells. These findings indicate basal stem/progenitor cells are the cells-of-origin of squamous carcinoma and that cooperation between Sox2 and microenvironment-activated Stat3 is required for Sox2-driven tumorigenesis.

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

“…Moreover, in the case of SOX2, which is expressed in adult stratified epithelia 18 , there is compelling evidence for its oncogenic role in human oesophageal squamous cell carcinomas (ESCCs) and mouse forestomach squamous cell carcinomas 19,54 . NANOG is also overexpressed in a number of human cancers, including ESCCs and head and neck squamous cells carcinomas (HNSCCs) 21,[42][43][44]53 .…”

Gpr177 regulates pulmonary vasculature development

“…The immunostaining and histochemistry were performed as previously described (Que et al, 2009;Rodriguez et al, 2010;Liu et al, 2013). The antibodies used for immunohistochemistry include: rabbit anti-Sox2 (Seven Hills), rabbit anti-Sox9 (Millipore), rabbit anti-cleaved caspase 3 (Cell Signaling), rat anti-Scgb1a1 (R&D), mouse anti-α-tubulin (Sigma), rabbit anti-SpC (Millipore), rat anti-T1a (Hamster), rat anti-phosphorylated Histone H3 (Sigma), rat anti-Pecam1 (BD Biosciences), rabbit anti-laminin (Sigma), rat anti-tenascin C (Abcam), rabbit anti-ABCA3 (Seven Hills), goat anti-Klf2 (Santa Cruz) and mouse anti-smooth muscle actin (Sigma).…”

“…Klf2 shRNA were purchased from Sigma-Aldrich. shRNA-mediated knockdown was performed as previously described (Liu et al, 2013). To test whether the Klf2 promoter is regulated by Wnt/β-catenin signaling, a 3 kb promoter region of the Klf2 gene was cloned into the pGL3 luciferase report vector, and then co-transfected into PAC1 cells with CatcLEF or Wnt3a plasmids.…”

Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells

“…The basal cell layer appears to be the primary source of Sox 2 expression implicated in de-velopment of squamous cell carcinoma of the esophagus (Liu et al 2013). The esophagus and trachea initially develop from a single tube and Sox 2 heterozygocity is associated with tracheoesophageal fistula.…”