Allen C. Gao

Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein–DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.

Interleukin-6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway

Interleukin‐6 (IL‐6) is a pleiotropic cytokine that regulates growth and differentiation of various types of malignant tumors, including prostate carcinomas. The levels of IL‐6 are elevated in sera of patients with metastatic prostate cancer. In this study, we evaluate the role of IL‐6 in the growth regulation of prostate cancer cells.

SELECTIVE ACTIVATION OF MEMBERS OF THE SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION FAMILY IN PROSTATE CARCINOMA

PURPOSEnCytokines, hormones and growth factors use signal transducers and activators of transcription (STAT) signaling pathways to control various biological responses, including development, differentiation, cell proliferation and survival. Constitutive activation of STATs has been found in a wide variety of human tumors. In this study we examined the activity of STATs in primary human prostate tissues.nnnMATERIALS AND METHODSnSTAT activity was determined in 104 human primary prostate tissues, including 42 tumors, 42 matched normal prostates adjacent to tumors and 20 normal prostates from donors without cancer by electromobility shift assay.nnnRESULTSnSignificant levels of activated Stat4 and Stat6 were detected in primary prostate tissues. However, little or no expression of active Stat1, Stat2 or Stat5 was detected in primary prostate tissues. Significantly higher levels of constitutive Stat6 activity were found in prostate carcinomas compared with levels in normal tissue adjacent to tumors and normal prostates from donors without prostate cancer. There was no significant difference in Stat6 activity in normal prostate tissues adjacent to tumors and normal prostates from donors without prostate cancer. The levels of Stat4 activity varied but failed to yield statistically significant differences among tumors, matched normal prostates adjacent to tumors and normal prostates from donors without cancer.nnnCONCLUSIONSnWe have previously shown that Stat3 is activated in prostate cancer. The results of the current study demonstrate that in addition to Stat3, Stat6 is selectively activated in prostate cancer.