title: Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.
abstract: JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small-molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: Department of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.affiliation: Department of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Meng-Yin
authors.initials: MY
authors.lastname: Hsieh
authors.affiliation: Department of Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Department of Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.affiliation: Department of Medical Oncology and Therapeutics Research, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Morgan
authors.affiliation: Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Wakabayashi
authors.affiliation: Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Dellinger
authors.affiliation: Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Han
authors.affiliation: Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. jyim@coh.org rjove@vgtifl.org.
authors.forename: John H
authors.initials: JH
authors.lastname: Yim
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. jyim@coh.org rjove@vgtifl.org.
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1