STAT3 is required but not sufficient for EGF receptor-mediated migration and invasion of human prostate carcinoma cell lines.
Growth factor-induced migration is a rate-limiting step in tumour invasiveness. The molecules that regulate this cellular behaviour would represent novel targets for limiting tumour cell progression. Epidermal growth factor (EGF) receptor (EGFR)-mediated motility, present in both autocrine and paracrine modes in prostate carcinomas, requires de novo transcription to persist over times greater than a few hours. Therefore, we sought to define specific signalling pathways that directly alter cellular transcription. Signal transducer and activator of transcription 3 (STAT3) is activated, as determined by electrophoretic motility shift assays, by EGFR in DU145 and PC3 human prostate carcinoma cells in addition to the motility model NR6 fibroblast cell line. Inhibition of STAT3 activity by antisense or siRNA downregulation or expression of a dominant-negative construct limited cell motility as determined by an in vitro wound healing assay and invasiveness through a extracellular matrix barrier. The expression of constitutively activated STAT3 did not increase the migration, which indicates that STAT3 is necessary but not sufficient for EGFR-mediated migration. These findings suggest that STAT3 signalling may be a new target for limiting prostate tumour cell invasion. In a microarray gene analysis of what transcription units are altered by EGF in a STAT3-dependent manner we found that the expression of motility-limiting VASP protein and the apoptosis nexus caspase 3 were both downregulated upon EGF exposure. These findings suggest a molecular basis for the STAT3 dependence of EGFR-mediated prostate tumour progression.
Zhou
W
W
Laboratory and Pathology Service, Pittsburgh VAMC, PA, USA.
Grandis
J R
JR
Wells
A
A
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000187:drug effects; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000096:biosynthesis / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098662:Vasodilator-Stimulated Phosphoprotein; D066246:ErbB Receptors; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases