Abstract
BackgroundWNT signaling pathways are significantly altered during cancer development. Vertebrates possess two classes of WNT signaling pathways: the “canonical” WNT/β-catenin signaling pathway, and the “non-canonical” pathways including WNT/Ca2+ and WNT/Planar cell polarity [PCP] signaling. WNT4 influences hematopoietic progenitor cell expansion and survival; however, WNT4 function in cancer development and the resulting implications for oncogenesis are poorly understood.The aim of this study was twofold: first, to determine the expression of WNT4 in mature peripheral blood cells and diverse leukemia-derived cells including cell lines from hematopoietic neoplasms and cells from patients with leukemia; second, to identify the effect of this ligand on the proliferation and apoptosis of the blast-derived cell lines BJAB, Jurkat, CEM, K562, and HL60.MethodsWe determined WNT4 expression by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) and T- and B-lymphocytes from healthy individuals, as well as from five leukemia-derived cell lines and blasts derived from patients with leukemia. To analyze the effect of WNT4 on cell proliferation, PBMCs and cell lines were exposed to a commercially available WNT4 recombinant human protein. Furthermore, WNT4 expression was restored in BJAB cells using an inducible lentiviral expression system. Cell viability and proliferation were measured by the addition of WST-1 to cell cultures and counting cells; in addition, the progression of the cell cycle and the amount of apoptosis were analyzed in the absence or presence of WNT4. Finally, the expression of WNT-pathway target genes was measured by qRT-PCR.ResultsWNT4 expression was severely reduced in leukemia-derived cell lines and blasts derived from patients with leukemia. The exposure of cell lines to WNT4 recombinant protein significantly inhibited cell proliferation; inducing WNT4 expression in BJAB cells corroborated this observation. Interestingly, restoration of WNT4 expression in BJAB cells increased the accumulation of cells in G1 phase, and did not induce activation of canonical WNT/β-catenin target genes.ConclusionsOur findings suggest that the WNT4 ligand plays a role in regulating the cell growth of leukemia-derived cells by arresting cells in the G1 cell cycle phase in an FZD6-independent manner, possibly through antagonizing the canonical WNT/β-catenin signaling pathway.
Highlights
WNT signaling pathways are significantly altered during cancer development
WNT4 is poorly expressed in leukemia-derived cells Because WNT4 expression has been related with the hematopoietic cell proliferation and differentiation, we wanted to know whether abnormal immature leukemic cells express WNT4
We compared the WNT4 expression in these cells with the usual level of expression found in peripheral blood mononuclear cells (PBMCs) from healthy volunteers
Summary
WNT signaling pathways are significantly altered during cancer development. Vertebrates possess two classes of WNT signaling pathways: the “canonical” WNT/β-catenin signaling pathway, and the “non-canonical” pathways including WNT/Ca2+ and WNT/Planar cell polarity [PCP] signaling. WNT pathways direct the specific activation of sets of genes regulating a plethora of cellular responses such as cell growth, differentiation, movement, migration, polarity, cell survival, and immune response. Signaling is initiated when WNT ligands bind to Frizzled (FZD) family receptors, activating a canonical signaling pathway in which the central player is a cytoplasmic protein called β-catenin. WNT ligands activate the so-called “non-canonical” pathways that are β-catenin-independent. These non-canonical pathways include the planar cell polarity (PCP) pathway that stimulates cytoskeletal reorganization, and the WNT-Ca2+ pathway that leads to calcium mobilization [4]. The canonical WNT/β-catenin signaling pathway has shown to exert a positive effect on the control of hematopoietic cell proliferation, survival, and differentiation. Abnormal activation of the WNT/β-catenin signaling pathway has been linked to the pathogenesis of many carcinomas and hematological malignancies [9,10,11,12]
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