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J Biol Chem. 2013 May 10;288(19):13842-9. doi: 10.1074/jbc.M113.450049. Epub 2013 Apr 2.

G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells.

Author information

1
Departments of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA.

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.

CONCLUSION:

JAK2/STAT3 signaling plays critical roles in BV8-mediated myeloid cell-dependent oncogenesis.

SIGNIFICANCE:

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.

KEYWORDS:

BV8; Myeloid Cell; STAT3; Signal Transduction; Tumor; shRNA

PMID:
23548897
PMCID:
PMC3650420
DOI:
10.1074/jbc.M113.450049
[Indexed for MEDLINE]
Free PMC Article
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