facilitating-drug-discovery-an-automated-high-content-inflammation

Facilitating Drug Discovery: An Automated High-content Inflammation Assay in Zebrafish

Zebrafish larvae are particularly amenable to whole animal small molecule screens1,2 due to their small size and relative ease of manipulation and ...

Acquired chromosomal aberrations, including gene copy number alterations, are involved in the development and progression of human malignancies. SOX2, a transcription factor-coding gene located at 3q26.33, is known to be recurrently and specifically amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity. In these organs, the SOX2 protein plays an important role in tumorigenesis and tumor survival. The aim of this study was to determine whether SOX2 amplification is also found in squamous cell carcinomas in other organs commonly affected by this tumor entity. In addition, we examined a large spectrum of lung cancer entities with neuroendocrine differentiation (ie, small cell cancers, large cell cancers, typical and atypical carcinoids) for SOX2 and TTF1 copy number gains to reveal potential molecular ties to squamous cell carcinomas or adenocarcinomas of the lung. Applying fluorescence in situ hybridization, we assessed squamous cell carcinomas of the cervix uteri (n = 47), the skin (n = 57), and the penis (n = 53) for SOX2 copy number alterations and detected amplifications in 28%, 28%, and 32% of tumors, respectively. Furthermore, we performed immunohistochemical SOX2 staining and found that SOX2 amplification is significantly associated with overexpression of the corresponding protein in squamous cell carcinomas (P < .001). Of the lung cancer entities with neuroendocrine differentiation, only small cell cancers and large cell cancers exhibited SOX2 or TTF1 amplifications at significant frequencies, indicating that at least a subset of these might be dedifferentiated forms of squamous cell carcinomas or adenocarcinomas of the lung. We conclude that SOX2 amplification and consequent SOX2 protein overexpression may represent important mechanisms of tumor initiation and progression in a considerable subset of squamous cell carcinomas.

SOX2 amplification is a common event in squamous cell carcinomas of different organ sites.

The transcription factor SOX2 (3q26.3-q27) is a key regulator of foregut development and an embryonic stem cell factor cooperating during induction of pluripotency in terminally differentiated somatic cells. Recently, we found SOX2 to be amplified in a subset of squamous cell lung and esophageal cancers. The aim of this study was to explore the prognostic role of SOX2 in a large series of squamous cell carcinomas and adenocarcinomas of the lung. A total of 891 samples from two independent population-based cohorts were assessed by fluorescence in situ hybridization and immunohistochemistry. Furthermore, we assessed for associations between SOX2 amplification/upregulation and clinicopathological features. Similar results were found in the two cohorts. Within squamous cell carcinoma cases, 8% high-level as well as 68 and 65% low-level SOX2 amplifications occurred in the two cohorts, respectively. In adenocarcinomas, no high-level amplification was found and low-level amplification occurred in 6% of the two cohorts. Within squamous cell carcinomas of one cohort, SOX2 amplification was associated with lower tumor grade, while higher levels of SOX2 expression were related to younger age, smaller tumor size, and lower probability of angiolymphatic invasion and metastasis. High SOX2 expression levels proved to be a marker for prolonged overall survival among patients with squamous cell carcinomas. In conclusion, SOX2 amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis.

Article	Year
Biomedizinische Technik. Biomedical engineering\| PubMed ID: 17155862	2006
Reproductive toxicology (Elmsford, N.Y.)\| PubMed ID: 19406227	2009
Nature methods\| PubMed ID: 19898487	2009
Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 20133847	2010
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc\| PubMed ID: 20473283	2010
Histopathology\| PubMed ID: 20636794	2010
Biomedizinische Technik. Biomedical engineering\| PubMed ID: 21210758	2011
SOX2 amplification is a common event in squamous cell carcinomas of different organ sites. Human pathology\| PubMed ID: 21334718	2011
SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc\| PubMed ID: 21460799	2011
Lung cancer (Amsterdam, Netherlands)\| PubMed ID: 21477882	2011
PloS one\| PubMed ID: 21655100	2011
Histopathology\| PubMed ID: 21707704	2011
Journal of cell science\| PubMed ID: 22331361	2012

Markus Reischl

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