Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin beta 6.
The persistent activation of signal transducer and activator of transcription 3 (Stat3) is a common feature of prostate cancer. However, little is known about the Stat3 targets that may mediate prostate tumorigenesis. The introduction of an activating mutant form of Stat3 (Stat3-C) into immortalized prostate epithelial cells resulted in tumorigenesis. Stat3-C-expressing cells had decreased E-cadherin levels, increased numbers of lamellipodia and stress fibers, and enhanced migratory capacities compared to vector control-expressing cells, with a concomitant increase in the expression of integrin beta6 and its ligand, fibronectin (FN). Exogenously added FN increased cellular migration, with a concomitant loss of E-cadherin expression. The blockade of integrin alphavbeta6 in Stat3-C-expressing cells inhibited migration, increased E-cadherin levels, and reduced colony formation in soft agar. These results demonstrate the sufficiency of constitutively activated Stat3 in mediating prostate tumorigenesis and identify novel Stat3 targets that are involved in promoting cell migration and transformation.
Azare
Janeen
J
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Leslie
Kenneth
K
Al-Ahmadie
Hikmat
H
Gerald
William
W
Weinreb
Paul H
PH
Violette
Shelia M
SM
Bromberg
Jacqueline
J
D015820:Cadherins / Q000032:analysis / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002999:Clone Cells; D004847:Epithelial Cells / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D039641:Integrin beta Chains / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000473:pathology; D011554:Pseudopodia / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D022502:Stress Fibers / Q000502:physiology
D015820:Cadherins; D005353:Fibronectins; D039641:Integrin beta Chains; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C072170:integrin beta6; D008156:Luciferases