title: Critical role of the WASF3 gene in JAK2/STAT3 regulation of cancer cell motility.
abstract: WASF3 has been shown to be required for invasion and metastasis in different cancer cell types and knockdown of WASF3 leads to suppression of invasion/metastasis. Aberrant signaling through the interleukin 6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) axis in cancer cells has emerged as a major mechanism for cancer progression. In this study, we demonstrate that interleukin 6 induces both WASF3 expression and phosphoactivation in breast and prostate cancer cell lines through the JAK2/STAT3 pathway in two different ways. First, we show that STAT3 binds directly to the WASF3 promoter and increases transcription levels, which correlates with increased migration potential. Inactivation of STAT3 with short hairpin RNA, dominant negative constructs or S3I-201 leads to reduced WASF3 levels and reduced migration. Second, we have shown that JAK2, while activating STAT3, also interacts with and activates WASF3. Inhibition of JAK2 with short hairpin RNA or AG490 leads to loss of migration due to reduced WASF3 activation levels and prevention of its membrane localization. Together, these results define a novel signaling network whereby JAK2/STAT3 signaling creates a feed-forward loop to raise activated WASF3 levels that promote cancer cell motility.
authors.affiliation: Georgia Health Sciences University Cancer Center, CN 2115, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.forename: Pushpankur
authors.initials: P
authors.lastname: Ghoshal
authors.forename: Lambert
authors.initials: L
authors.lastname: Ngoka
authors.forename: Yun
authors.initials: Y
authors.lastname: Mei
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics* / Q000378:metabolism
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; D015850:Interleukin-6; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; C507924:JAK2 protein, human; D053614:Janus Kinase 2