title: G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells.
abstract: BACKGROUND
  Signaling pathways underlying BV8-mediated oncogenesis remain unknown.
  
  
  RESULTS
  BV8-STAT3 forms a feed-forward loop in both normal and malignant myeloid cells and promotes tumor growth.
  
  
  CONCLUSIONS
  JAK2/STAT3 signaling plays critical roles in BV8-mediated myeloid cell-dependent oncogenesis.
  
  
  CONCLUSIONS
  This study identifies a novel role of BV8-STAT3 signaling in mediating cross-talk between tumor microenvironment and tumor cells. An important role of BV8 in mobilization of myeloid cells and myeloid cell-dependent angiogenesis has been established. Recently, it has also been shown that granulocyte colony-stimulating factor (G-CSF)-induced BV8 expression is STAT3 dependent in CD11b(+)Gr1(+) myeloid cells. However, the BV8 downstream signaling pathway(s) intrinsic to myeloid cells crucial for angiogenesis, and potentially also for development of cancers of myeloid origin, remains largely unknown. Here we show that BV8 activates STAT3, which is critical for regulating genes important for both tumor cell proliferation/survival and tumor angiogenesis, in both normal and malignant myeloid cells. Further, BV8-induced STAT3 activation requires Janus-activated kinase 2 (JAK2) activity as shown by both genetic and pharmacologic inhibition. Knocking down BV8 in human myeloid leukemia cells inhibits STAT3 activity and expression of STAT3 downstream angiogenic and pro-proliferation/survival genes, leading to a decrease in tumor cell viability. BV8 shRNA expressing leukemia cells exhibit reduced STAT3 activity and tumor growth in vivo. Taken together, we have delineated a signaling pathway downstream of BV8 that plays critical roles in both the tumor microenvironment and malignant myeloid cells for angiogenesis and tumor cell proliferation/survival.
authors.affiliation: Departments of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Rongze
authors.initials: R
authors.lastname: Lu
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shudan
authors.initials: S
authors.lastname: Shen
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D025461:Feedback, Physiological; D005768:Gastrointestinal Hormones / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D022423:Myeloid Cells / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D042501:Angiogenic Proteins; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: BV8; Myeloid Cell; STAT3; Signal Transduction; Tumor; shRNA
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