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Stat3 is required for the development of skin cancer
Laura Pedranzini, Andrea Leitch, and Jacqueline Bromberg
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Address correspondence to: Jacqueline Bromberg, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Phone: (212) 639-8191; Fax: (212) 422-2231; E-mail: bromberj@mskcc.org.
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Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Address correspondence to: Jacqueline Bromberg, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Phone: (212) 639-8191; Fax: (212) 422-2231; E-mail: bromberj@mskcc.org.
Find articles by Leitch, A. in: PubMed | Google Scholar
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Address correspondence to: Jacqueline Bromberg, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Phone: (212) 639-8191; Fax: (212) 422-2231; E-mail: bromberj@mskcc.org.
Find articles by Bromberg, J. in: PubMed | Google Scholar
Published September 1, 2004 - More info
J Clin Invest. 2004;114(5):619–622. https://doi.org/10.1172/JCI22800.
© 2004 The American Society for Clinical Investigation
Stat’s (signal transducers and activators of transcription) are a family of latent transcription factors that are activated in response to many cytokines and growth factors. Stat activation is dependent upon tyrosine phosphorylation, which induces dimerization via reciprocal phosphotyrosine–src homology domain 2 (phosphotyrosine–SH2) interaction between two Stat molecules. Activated Stat’s translocate to the nucleus where they bind to consensus promoter sequences of target genes and activate their transcription (1) (Figure 1). Many tyrosine kinases, including JAKs (Janus kinases), RTKs (receptor tyrosine kinases), and non-RTKs can phosphorylate Stat proteins. In normal cells, Stat tyrosine phosphorylation is transient, lasting from 30 minutes to several hours. However, in numerous cancer-derived cell lines or in primary tumors, Stat proteins (in particular Stat3) are persistently tyrosine phosphorylated either as a consequence of deregulated positive effectors of Stat activation such as tyrosine kinases or negative regulators of Stat phosphorylation, e.g., phosphatases, suppressor of cytokine signaling, protein inhibitor of activated stats) (2). Inhibition of Stat3 activity in tumor-derived cell lines by the introduction of antisense, small interfering RNA, dominant-negative Stat3 constructs, and/or blockade of tyrosine kinases has been associated with growth arrest and apoptosis (2). Furthermore, the introduction of a constitutively activated Stat3 molecule (Stat3C) into immortalized cell lines leads to transformation, indicating an oncogenic role for activated Stat3 (3, 4). A possible mechanism for transformation by activated Stat3 is the transcriptional upregulation of genes known to be involved in proliferation and apoptosis, including Bcl-xL, c-Myc, cyclin D1, Vegf, and Survivin (3, 5–8). In addition to its role as a transcription factor, phosphorylated Stat3 has been described in a recent report as a component of focal adhesions (sites of cell contact with the extracellular matrix) that may contribute to the invasiveness of ovarian cancer cells (9). The in vivo role of Stat3 in tumorigenesis has not been addressed until now. In this issue of the JCI, Chan and colleagues demonstrate in two different murine models of skin tumor development that Stat3 is required for de novo tumorigenesis (10).
Figure 1Model 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.
One of the best-established model systems for studying the mechanisms underlying the process of malignant transformation is the mouse skin model of multistage carcinogenesis (11, 12) (Figure 2). In this model, the process of skin tumor development can be subdivided into three different stages: initiation, promotion, and progression. Initiation is typically induced by the topical application of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Interestingly, in DMBA-treated epidermal cells, one usually finds mutations within the Harvey rat sarcoma virus oncogene (Ha-ras) gene. These mutations, however, are not sufficient to induce de novo transformation. Promotion of tumorigenesis is generated by the topical application of phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) to the skin, leading to epithelial cell proliferation with a concomitant increased expression of the ligand EGF as well as of cyclin D1, c-Jun, c-Fos, and c-Myc (13–16). TPA-treated mice form multiple benign papillomas within 10–20 weeks. Tumor progression is a spontaneous process resulting in the formation of malignant squamous carcinomas.
Figure 2Two-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.
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