SOX-2 IN SQUAMOUS CARCINOMA

October 5, 2009 — A new study is the first to report that SOX2 — a member of the developmentally important SOX family of genes — functions as an amplified oncogene in squamous cell carcinomas (SCCs) of the lung and esophagus. SOX2, an "amplified lineage-survival oncogene" in these cancers, is activated by changes in the DNA of cells in which it normally plays a developmental role. The findings suggest common pathways in normal development, cancer, and cellular pluripotency.

The study, published online October 4 in Nature Genetics, was led by senior author Matthew L. Meyerson, MD, PhD, from the Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute and the Department of Pathology, Harvard Medical School in Boston; and the Broad Institute in Cambridge, Massachusetts. It involved the collaboration of several American institutions and researchers in Canada, Brazil, Germany, and Norway.

The primary focus of the investigation was to find genomic abnormalities in SCCs of the esophagus and lung. DNA samples were obtained from 40 esophageal SCCs and 47 lung SCCs and scored for recurrent genomic gains or losses.

In lung SCCs, the greatest peak of genomic amplification was on the long arm of chromosome 3 (3q26.33); the next largest peaks were on chromosome 7p (including gene EGFR) and chromosome 8p (including FGFR1). In esophageal SCCs, the greatest amplification peak was on chromosome 11q (including gene CCND1); other amplified regions were located at EGFR, at FGFR1, on chromosome 8q, and at chromosome segment 3q26.33 — the same region noted in lung SCCs.

Closer analysis showed segment 3q26.33 to be amplified in 6 of 40 esophageal SCCs and in 11 of 47 lung SCCs (genomic amplification was defined as copy number ≥ 3.6). Only 1 gene (SOX2) was included in the 3q amplification peak of esophageal samples, whereas 4 genes (including SOX2) were in the amplified region of lung SCCs. When messenger (m)RNA levels were measured in 27 lung SCCs, the samples with amplified SOX2 demonstrated greater SOX2 mRNA expression (P = .001). A similar correlation was found in esophageal SCCs.

The interaction of SOX2 and short hairpin (sh)RNAs influenced the proliferation of SCC cell lines. The authors note that "several independent shRNAs targeting SOX2 reduced proliferation of the SCC cell lines" and that "suppression of SOX2 has the largest differential antiproliferative effects on the 3q26.33 amplified SCC cell lines among all genes tested." In addition, the role of SOX2 in cell proliferation is supported by the observation that SOX2-directed shRNA constructs decreased proliferation of cell lines with amplified SOX2, but not in control lines with low SOX2 expression.

Although this study investigated interactions between SOX2 and other genes, the authors conclude that SOX2 may be transformative with many cooperative genes, but "further work will be required to elaborate the genes that can act with SOX2 in tumorigenesis and the subtypes of tumors in which these genes are active."

SOX2 has been previously recognized as a major factor in pluripotency — the potential of a cell to develop into more than 1 type of mature cell. The study investigated how this role contributes to the oncogenic activity of SOX2. In a lung adenocarcinoma cell line, SOX2 activity was found to promote squamous identity instead of a loss of cellular differentiation (which would lead to a pluripotent state). The authors consider this to be consistent with the role of SOX2 as a "lineage-survival oncogene."

In light of the complex actions of SOX2 in regulating normal development, proliferation, and response to injury, and its influence on multiple cell types, the report suggests that "the elucidation of SOX2-dependent pathways . . . may identify new therapeutic vulnerabilities in SCC and uncover additional common pathways between cancer, normal development, and the maintenance of pluripotency."

Nat Genet. Published online October 4, 2009.