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      Evidence That SOX2 Overexpression Is Oncogenic in the Lung

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          Abstract

          Background

          SOX2 (Sry-box 2) is required to maintain a variety of stem cells, is overexpressed in some solid tumors, and is expressed in epithelial cells of the lung.

          Methodology/Principal Findings

          We show that SOX2 is overexpressed in human squamous cell lung tumors and some adenocarcinomas. We have generated mouse models in which Sox2 is upregulated in epithelial cells of the lung during development and in the adult. In both cases, overexpression leads to extensive hyperplasia. In the terminal bronchioles, a trachea-like pseudostratified epithelium develops with p63-positive cells underlying columnar cells. Over 12–34 weeks, about half of the mice expressing the highest levels of Sox2 develop carcinoma. These tumors resemble adenocarcinoma but express the squamous marker, Trp63 (p63).

          Conclusions

          These findings demonstrate that Sox2 overexpression both induces a proximal phenotype in the distal airways/alveoli and leads to cancer.

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          Basal cells as stem cells of the mouse trachea and human airway epithelium.

          Jason R. Rock, Mark Onaitis, Emma L. Rawlins … (2009)
          The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.
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            p63 Is essential for the proliferative potential of stem cells in stratified epithelia.

            Makoto Senoo, Filipa C.S.C. Pinto, Christopher Crum … (2007)
            The distinguishing feature of adult stem cells is their extraordinary capacity to divide prior to the onset of senescence. While stratified epithelia such as skin, prostate, and breast are highly regenerative and account disproportionately for human cancers, genes essential for the proliferative capacity of their stem cells remain unknown. Here we analyze p63, a gene whose deletion in mice results in the catastrophic loss of all stratified epithelia. We demonstrate that p63 is strongly expressed in epithelial cells with high clonogenic and proliferative capacity and that stem cells lacking p63 undergo a premature proliferative rundown. Additionally, we show that p63 is dispensable for both the commitment and differentiation of these stem cells during tissue morphogenesis. Together, these data identify p63 as a key, lineage-specific determinant of the proliferative capacity in stem cells of stratified epithelia.
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              Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm.

              Jianwen Que, Edward Morrisey, James Goldenring … (2007)
              Sox2 is expressed in developing foregut endoderm, with highest levels in the future esophagus and anterior stomach. By contrast, Nkx2.1 (Titf1) is expressed ventrally, in the future trachea. In humans, heterozygosity for SOX2 is associated with anopthalmia-esophageal-genital syndrome (OMIM 600992), a condition including esophageal atresia (EA) and tracheoesophageal fistula (TEF), in which the trachea and esophagus fail to separate. Mouse embryos heterozygous for the null allele, Sox2(EGFP), appear normal. However, further reductions in Sox2, using Sox2(LP) and Sox2(COND) hypomorphic alleles, result in multiple abnormalities. Approximately 60% of Sox2(EGFP/COND) embryos have EA with distal TEF in which Sox2 is undetectable by immunohistochemistry or western blot. The mutant esophagus morphologically resembles the trachea, with ectopic expression of Nkx2.1, a columnar, ciliated epithelium, and very few p63(+) basal cells. By contrast, the abnormal foregut of Nkx2.1-null embryos expresses elevated Sox2 and p63, suggesting reciprocal regulation of Sox2 and Nkx2.1 during early dorsal/ventral foregut patterning. Organ culture experiments further suggest that FGF signaling from the ventral mesenchyme regulates Sox2 expression in the endoderm. In the 40% Sox2(EGFP/COND) embryos in which Sox2 levels are approximately 18% of wild type there is no TEF. However, the esophagus is still abnormal, with luminal mucus-producing cells, fewer p63(+) cells, and ectopic expression of genes normally expressed in glandular stomach and intestine. In all hypomorphic embryos the forestomach has an abnormal phenotype, with reduced keratinization, ectopic mucus cells and columnar epithelium. These findings suggest that Sox2 plays a second role in establishing the boundary between the keratinized, squamous esophagus/forestomach and glandular hindstomach.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2010
                Publication date (Electronic): 10 June 2010
                Volume: 5
                Issue: 6
                Electronic Location Identifier: e11022
                Affiliations
                [1 ]Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America
                [2 ]Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, United States of America
                University of Barcelona, Spain
                Author notes

                Conceived and designed the experiments: YL CRF JRR BLMH MWO. Performed the experiments: YL CRF JRR XX WW MWO. Analyzed the data: YL CRF JRR BLMH MWO. Contributed reagents/materials/analysis tools: YL CRF JRR BLMH MWO. Wrote the paper: YL CRF BLMH MWO.

                Article
                Publisher ID: 10-PONE-RA-17096R1
                DOI: 10.1371/journal.pone.0011022
                PMC ID: 2883553
                PubMed ID: 20548776
                SO-VID: af279990-9a03-4323-a981-4a1d2f038aa6
                Copyright © Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 15 March 2010
                Date accepted : 16 May 2010
                Page count
                Pages: 12
                Categories
                Subject: Research Article
                Subject: Cell Biology
                Subject: Cell Biology/Gene Expression
                Subject: Genetics and Genomics/Cancer Genetics
                Subject: Genetics and Genomics/Disease Models
                Subject: Genetics and Genomics/Gene Expression
                Subject: Genetics and Genomics/Genomics
                Subject: Genetics and Genomics/Medical Genetics
                Subject: Oncology/Lung Cancer
                Subject: Respiratory Medicine/Lung Cancer

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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