SOX2 Is an Oncogene Activated by Recurrent 3q26.3 Amplifications in Human Lung Squamous Cell Carcinomas

Abstract

Squamous cell carcinoma (SCC) of the lung is a frequent and aggressive cancer type. Gene amplifications, a known activating mechanism of oncogenes, target the 3q26-qter region as one of the most frequently gained/amplified genomic sites in SCC of various types. Here, we used array comparative genomic hybridization to delineate the consensus region of 3q26.3 amplifications in lung SCC. Recurrent amplifications occur in 20% of lung SCC (136 tumors in total) and map to a core region of 2 Mb (Megabases) that encompasses SOX2, a transcription factor gene. Intense SOX2 immunostaining is frequent in nuclei of lung SCC, indicating potential active transcriptional regulation by SOX2. Analyses of the transcriptome of lung SCC, SOX2-overexpressing lung epithelial cells and embryonic stem cells (ESCs) reveal that SOX2 contributes to activate ESC-like phenotypes and provide clues pertaining to the deregulated genes involved in the malignant phenotype. In cell culture experiments, overexpression of SOX2 stimulates cellular migration and anchorage-independent growth while SOX2 knockdown impairs cell growth. Finally, SOX2 over-expression in non-tumorigenic human lung bronchial epithelial cells is tumorigenic in immunocompromised mice. These results indicate that the SOX2 transcription factor, a major regulator of stem cell function, is also an oncogene and a driver gene for the recurrent 3q26.33 amplifications in lung SCC.

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

“…11 Besides its role during neurogenesis and embryonic foregut development, SOX2 can aid the reprogramming of adult cells into induced pluripotent stem cells, indicating a major potency for induction of cellular fate changes. 12,14,28 More recently, studies have identified SOX2 as the driving gene of the well-known 3q amplicon in squamous cell carcinomas of the lung and the esophagus, suggesting SOX2 as a novel candidate oncogene 9,10 in lung carcinogenesis.…”

“…9,10,17 These variations in frequency are most likely due to methodological discrepancies applied by different laboratories (eg the molecular method applied for detection of SOX2 copy number status and the threshold set to distinguish between different levels of amplification). Furthermore, differences between the cohorts and tumor heterogeneity have to be considered.…”

“…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.…”