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

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. He...

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Bibliographic Details
Published in:Cell stem cell 2013-03, Vol.12 (3), p.304-315
Main Authors: Liu, Kuancan, Jiang, Ming, Lu, Yun, Chen, Hao, Sun, Jun, Wu, Shaoping, Ku, Wei-Yao, Nakagawa, Hiroshi, Kita, Yoshiaki, Natsugoe, Shoji, Peters, Jeffrey H., Rustgi, Anil, Onaitis, Mark W., Kiernan, Amy, Chen, Xiaoxin, Que, Jianwen
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Humans
Inflammation - metabolism
Mice
SOXB1 Transcription Factors - genetics
SOXB1 Transcription Factors - metabolism
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
Stem Cells - metabolism
Stem Cells - pathology
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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 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 that 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. [Display omitted] ► Sox2+ve basal stem/progenitor cells self-renew and differentiate in vitro and in vivo ► Conditional Sox2 overexpression promotes the expansion of basal progenitor cells ► Sox2 cooperates with an inflammatory microenvironment to induce squamous cancer ► Sox2 and Stat3 together transform mouse and human esophageal progenitor cells Sox2 cooperates with microenvironmental STAT3 in the forestomach to transform basal progenitor cells and initiate squamous cell carcinoma.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2013.01.007