Using such conditional STAT3 knockout mice, it has been shown that STAT3 is required AZ 960 for tumorigenesis in mouse skin, intestine and liver. Such results left little doubt that STAT3 is a critical oncogenic transcription factor and an attractive target for cancer therapy. We used hepatocyte specific STAT3 deficient mice to examine the role of STAT3 in DEN induced liver tumorigenesis. Stat3?hep mice were found to exhibit more than a 6 fold reduction in HCC load relative to Stat3F/F mice. Furthermore, tumors in Stat3?hep mice were smaller, suggesting that STAT3 may play a role in HCC cell proliferation and/or survival. We derived cell lines from DEN induced HCCs of Stat3F/F mice.
Deletion of STAT3 in cultured Stat3F/F dih cells, accomplished by infecting the cells with a Cre expressing adenovirus, resulted in cell BMS 777607 death, suggesting that activated STAT3 is required for the survival of HCC cells. Although dih cells that are completely STAT3 deficient cannot survive, cells with a partial reduction of STAT3 expression, accomplished by shRNA transduction are viable, but exhibit a senescent phenotype and fail to form subcutaneous tumors upon transplantation. Interestingly, dependence on STAT3 for survival is also seen in anaplastic large cell lymphomas that spontaneously appear in NPM ALK transgenic mice, which invariably show STAT3 activation. The lymphoma cells rapidly die when depleted of STAT3 in vitro. Given this strict dependence on STAT3 for survival, it is puzzling to find that a few tumors can still develop in the complete absence of STAT3 in both the DEN induced HCC model and in NPM ALK transgenic mice.
It is plausible that an alternative pathway can be activated in STAT3 null tumors but this pathway is hardly active in the presence of STAT3. STAT3 as a therapeutic target in human HCC As compelling data continue to accumulate STAT3 has become an attractive molecule target for the treatment and prevention of human malignancies. While safety is a primary concern, given the embryonic lethality of STAT3 null mice, with the use of STAT3 inhibitors, tissue specific Stat3 ablation experiments indicate that STAT3 is not required for the survival of differentiated cells. These results provide supportive evidence that it may be safe to target STAT3 for human cancer therapy.
Different types of STAT3 inhibitors were designed to either directly target STAT3 by inhibiting its dimerization, DNA binding, or nuclear entry or through the targeting of upstream components in the STAT3 activation pathway. S3I 201 is a direct STAT3 inhibitor that blocks both STAT3 dimerization and DNA binding and transcriptional activities. Treatment of tumor xenografts derived from a human breast cancer cell line with constitutive STAT3 activity with S3I 201 resulted in inhibition of tumor growth. The therapeutic effect of S3I 201 on xenografts of the human HCC cell line Huh 7 was also examined and it was found that at a dose of 5 mg/kg given every other day, S3I 201 inhibited STAT3 tyrosine phosphorylation and tumor growth. Another widely used STAT3 inhibitor is AG490 which blocks activation of STAT3 by inhibiting the upstream kinase JAK2. We have tested the effect of S3I 201 and AG490 on the in vivo tumorigenic growth of dih cells and found effective inhibition of S