Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.

نویسندگان

  • Wei Wen
  • Wei Liang
  • Jun Wu
  • Claudia M Kowolik
  • Ralf Buettner
  • Anna Scuto
  • Meng-Yin Hsieh
  • Hao Hong
  • Christine E Brown
  • Stephen J Forman
  • David Horne
  • Robert Morgan
  • Mark Wakabayashi
  • Thanh H Dellinger
  • Ernest S Han
  • John H Yim
  • Richard Jove
چکیده

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.

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عنوان ژورنال:
  • Molecular cancer therapeutics

دوره 13 12  شماره 

صفحات  -

تاریخ انتشار 2014