SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Abstract

Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development.1,2 Here we show that a peak of genomic amplification on chromosome 3q26.33, found in squamous cell carcinomas (SCCs) of the lung and esophagus, contains the transcription factor gene SOX2—which is mutated in hereditary human esophageal malformations3 and necessary for normal esophageal squamous development4, promotes differentiation and proliferation of basal tracheal cells5 and co-operates in induction of pluripotent stem cells.6,7,8 SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These observations identify SOX2 as a novel lineage survival oncogene in lung and esophageal SCC.

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

“…8 Recently, we and others identified the transcription factor SOX2 (SRY (sex determining region Y)-box 2) as the most promising candidate disease-related gene within this amplicon. 9,10 SOX2 is a member of the SRY-related HMG-box (SOX) family of transcription factors 11 and has been recently studied for its ability to reprogram adult cells into induced pluripotent stem cells when coexpressed with other embryonic stem cell factors like Nanog and Oct3/4. 12 SOX2 is expressed during early embryogenesis and has an important role in embryonic and extra-embryonic cell types.…”

“…17 In lung cancer, SOX2 amplification and expression can be found in a large subset of squamous cell carcinomas. 9,10,17,18 Though at much lower frequencies, expression of SOX2 has also been reported to occur in adenocarcinomas of the lung. [17][18][19] In vitro studies suggest that SOX2 upregulation induces cell proliferation and anchorage-independent growth in squamous cell lung cancer cell lines.…”

“…[17][18][19] In vitro studies suggest that SOX2 upregulation induces cell proliferation and anchorage-independent growth in squamous cell lung cancer cell lines. 9,10 Furthermore, SOX2 amplification and expression have been detected in preinvasive lesions of the lung, such as squamous dysplasia and carcinoma in situ. 17,20 SOX2 may have similar oncogenic effects in other organs of foregut and non-foregut origin, since amplification and expression also occur in squamous cell carcinomas of the oral cavity, as well as in esophageal and gastric tumors.…”

“…17,20 SOX2 may have similar oncogenic effects in other organs of foregut and non-foregut origin, since amplification and expression also occur in squamous cell carcinomas of the oral cavity, as well as in esophageal and gastric tumors. 9,[21][22][23] Recently, SOX2 expression has been detected in early-stage breast carcinoma. 24 These data suggest that expression of SOX2 drives oncogenesis and therefore overexpression in tumors may be associated with a more aggressive tumor phenotype and poorer clinical outcome.…”

Fountain of youth for squamous cell carcinomas? On the epigenetic age of non‐small cell lung cancer and corresponding tumor‐free lung tissues

“…One of the enriched genes from the gene sets with a strong negative correlation with DNAm age was SOX2. SOX2 is involved in the pluripotency of human embryonic stem cells15, 16 and is indicative of squamous histology17 as well as being an antagonist of the tumor‐suppressive Hippo pathways, leading to maintenance of cancer stem cells18 (CSCs). This observation might reflect the nature of lung SQC, exhibiting an increased stem cell activity accompanied by decreased DNAm age, as possible CSC populations have been identified in NSCLC cell lines and tissues,19 with SQC exhibiting a higher fraction of stem cells leading to speculation about the respective cells of origin 20.…”