Evidence That SOX2 Overexpression Is Oncogenic in the Lung

Abstract

BackgroundSOX2 (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 FindingsWe 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).ConclusionsThese findings demonstrate that Sox2 overexpression both induces a proximal phenotype in the distal airways/alveoli and leads to cancer.

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

“…17 Furthermore, McCaughan et al 20 reported SOX2 amplification in none of a series of low-grade bronchial lesions, but in all high-grade lesions, suggesting upregulation during preinvasive disease progression. Consistently, Lu et al 25 showed that conditional homozygous SOX2 overexpression in clara cells induces bronchial epithelial hyperplasia with 50% of cases showing a progression to lung cancer in mice.…”

“…These results support our previous findings, indicating that patients with lung squamous cell carcinomas harboring an embryonic stem cell-like gene expression signature, including SOX2 expression, exhibit significant better survival than patients with tumors lacking this signature. 9 Consistently, Lu et al 25 were able to show in a cohort of early stage lung squamous cell carcinomas that patients with SOX2 expression above the median show prolonged overall survival.…”

“…In support of this, SOX2 proved to be significantly co-expressed with typical markers of squamous cell carcinoma differentiation, such as p63. 9,15,25 Besides the lung, SOX2 has been found to be amplified and expressed in squamous cell carcinomas originating from other organ sites, predominantly derived from the embryonic foregut. 9,21,22 Recently, we found SOX2 to be amplified and expressed in squamous cell carcinomas originating from non-foregut tissues, such as the skin, the cervix, and the penis, 23 indicating that SOX2 might be a general marker for squamous cell carcinoma differentiation regardless the tissue of origin.…”

“…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. However, in lung cancers, contradictory results have been reported so far: while one smaller study suggested that higher SOX2 expression is associated with better outcome in patients suffering from lung squamous cell carcinomas, 25,26 data from a third group present SOX2 expression to be a marker of poor prognosis in stage I lung adenocarcinomas. 19 Together, these findings support the notion that SOX2 upregulation has a major impact on lung cancer initiation and progression.…”

Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract

“…Sex determining region-Y-related high mobility group box (SOX) 2 is a transcription factor that is involved in the maintenance of embryonic stem cell pluripotency and in multiple developmental processes. It is overexpressed in certain poorly differentiated subtypes of cancer (eg, lung, 24,25 breast, 26,27 and colorectal 28,29 cancers). SOX2 is not only a prognostic indicator in these cancers but also a candidate for cancer stem-like cell/tumor-initiating cell-targeting T-cell-based immunotherapy.…”