In addition to their central roles in normal cell signaling, recent studies have demonstrated that diverse oncoproteins can activate specific STATs (particularly Stat3 and Stat5) and that constitutively-activated STAT signaling directly contributes to oncogenesis.
These findings provide evidence that constitutively activated Stat3 is an early event in head and neck carcinogenesis that contributes to the loss of growth control by an anti-apoptotic mechanism.
In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.
Stat-3 activation is an early event in head and neck carcinogenesis though its role in blocking the apoptosis in vivo in solid tumors was not observed.
Because constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been linked to carcinogenesis of various tumors including head and neck SCCa, we studied whether sulindac treatment affects the Stat3 signaling pathway in oral SCCa cells.
Activation of NF-kB and STAT-3 most likely contribute to the progression of viral infections to chronic hepatitis and liver oncogenesis associated with HBV and HCV infections.
Since Stat3 appears to play an important role in breast cancer, it is of interest to investigate Stat3-regulated genes and elucidate Stat3-mediated oncogenesis.
As downstream targets of the PTEN and EGFR signaling pathways, Akt, NFkappaB, and signal transducer and activator of transcription-3 (Stat3) have been shown to play important roles in the control of cell proliferation, apoptosis, and oncogenesis.
Aberrant Stat3 promotes uncontrolled growth and survival through dysregulation of gene expression, including cyclin D1, c-Myc, Bcl-xL, Mcl-1 and survivin genes, and thereby contributes to oncogenesis.
In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D.
Our findings illustrate the biological importance of JAK3/STAT3 activation in the oncogenesis of colon cancer and provide novel evidence that JAK3 is expressed and contributes to STAT3 activation in this malignant neoplasm.
To further address the role of Stat3 in skin SCC tumorigenesis, we have analyzed a panel of human skin-derived cell lines ranging from normal human epidermal keratinocytes (NHEK), to non-tumorigenic transformed skin cells (HaCaT), to highly tumorigenic cells (SRB1-m7 and SRB12-p9) and observed a positive correlation between Stat3 phosphorylation and SCC malignancy.
Signal-transducer-and-activator-of-transcription-3 (STAT3), a member of a family of six different transcription factors, is closely linked with tumorigenesis.
Specific suppression of phosphorylated STAT3 reduced its DNA-binding activity, inhibited the expression of vascular endothelial growth factor, survivin, matrix metalloproteinases 2 and 9, reduced cell proliferation and migratory potential, induced apoptosis in vitro, and inhibited intradermal angiogenesis and s.c. tumorigenesis upon injection in mice.
These findings demonstrate that Stat3 plays a critical role in the tumorigenesis, but not in the cell survival, of SCC cells and suggest that additional pro-apoptotic signals are necessary for the induction of apoptosis.
Strikingly, STAT3 translocates to the nucleus and interacts with WT1 in a variety of primary Wilms' tumor cells, raising the hypothesis that WT1 and activated STAT3 in Wilms' tumor accelerate tumorigenesis.