Stat3 is required for the development of skin cancer

Abstract

Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is constitutively activated in a variety of human malignancies, including prostate, lung, brain, breast, and squamous cell carcinomas. Inhibition of activated Stat3 leads to decreased proliferation and apoptosis of many cancer-derived cell lines, while the introduction of a constitutively activated form of Stat3 into immortalized human breast epithelial cells and rodent fibroblasts results in cellular transformation. Collectively, these data suggest a role for Stat3 in oncogenesis. A new study from Chan et al. is the first to demonstrate a requirement for Stat3 in de novo epithelial carcinogenesis in vivo. Using the two-step model of chemically induced skin carcinogenesis, the authors demonstrated that mice deficient in Stat3 were completely resistant to skin tumor development.

Figure 1

Model for Stat3 signaling. Stat3 is a transcription factor, which is activated in response to many cytokines and growth factors that bind to specific receptors. Upon ligand-receptor binding, Stat3 is recruited to the plasma membrane, where it becomes activated via phosphorylation of a tyrosine residue either directly by RTKs, such as the PDGF receptor and EGF receptor, or by non-RTKs, such as Src and JAK. Stat3 activation induces dimerization via reciprocal phosphotyrosine–SH2 interaction between two Stat3 molecules. The Stat3 dimers then translocate to the nucleus where they bind to consensus sequences on the promoter of target genes and activate their transcription. Stat3 activation is tightly regulated by different negative regulators of phosphorylation, such as phosphatases, suppressor of cytokine signaling, and protein inhibitor of activated Stats. In many cancer-derived cell lines and primary tumors Stat3 is constitutively activated either as a consequence of deregulated signaling from positive effectors (e.g., overexpression of growth factor receptors and their ligands) or by abnormal activity of negative effectors. SOCS, suppressor of cytokine signaling; PIAS, protein inhibitor of activated Stats.

Figure 2

Two-step model of chemically induced carcinogenesis and proposed role of Stat3 in preventing tumorigenesis. Initiation is achieved by topical application of the carcinogen DMBA, which binds to DNA and typically induces mutations in the Ha-ras gene. The result of this process is the formation of an initiated cell. During this stage Stat3 protects the keratinocytes and the initiated cells from DNA damage–induced apoptosis. Promotion involves repeated application of a noncarcinogenic promoter, TPA, leading to clonal expansion of the initiated cell. This process results in the formation of multiple benign papillomas. Stat3 is essential for the proliferation of the initiated cells after TPA treatment and for the maintenance of the preoncogenic lesions. Progression is a spontaneous process characterized by the accumulation of additional genetic changes (i.e., elevated expression of genes encoding Ha-ras and cyclin D1; loss of functional p53), which accelerate the conversion of benign papillomas to malignant carcinomas. The pink cells represent initiated cells bearing Ha-ras mutations; the purple cells represent cells that have acquired multiple genetic changes.