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author:("Dai, bonghan")
1.  Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC) 
Cancer Biology & Therapy  2011;12(10):872-880.
Angiogenesis is essential for tumor growth and metastasis. VEGF has been shown to be a central player in this process. The biological activity of VEGF is mainly mediated by two tyrosine kinase receptors, VEGFR-1 and VEGFR-2. While increasing evidence suggests that VEGF/VEGFR-1 signaling is crucial for tumor angiogenesis, its molecular mechanism is not well understood. Here we show that VEGFR-1 knockdown dramatically inhibits tumor growth. This inhibition is associated with significant decrease of tumor VEGF levels and tumor angiogenesis as well as an increased tumor necrosis. Moreover, we demonstrate that VEGF in CRCC tumors is mainly produced by tumor stromal cells instead of the tumor cells themselves. It has been shown that macrophages constitute a significant part of tumor stromal cells and produce a large amount of VEGF. We therefore examined the macrophage infiltration in the xenograft tumors. Remarkably, VEGFR-1 knockdown attenuates the tumor macrophages infiltration. To understand the mechanism, we investigated the impact of VEGFR-1 knockdown on the expression of monocyte chemoattractant protein-1 (MCP-1), one of the main chemoattractants for macrophages. Significantly, VEGFR-1 knockdown inhibits MCP-1 expression of CRCC cells. Taken together, these data indicate that VEGF/VEGFR-1 signaling plays an essential role in initiating tumor angiogenesis by regulating MCP-1 expression, which in turn, attracts macrophages infiltration and VEGF production. Thus, these studies suggest that blockade of VEGFR-1 function may provide a tumor-specific, VEGF-based therapeutic strategy for treatment of CRCC.
PMCID: PMC3280902  PMID: 21989163
VEGF receptor 1; angiogenesis; tumor macrophage infiltration; monocyte chemoattractant protein-1 (MCP-1); tumor-specific therapy; angiogenic switch; and clear cell renal cell carcinoma (CRCC)
2.  Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease 
BMC Nephrology  2012;13:109.
Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity. We investigated the role of these increases on cystic disease progression in PKD kidneys.
We examined the role of type I collagen (collagen I) and membrane bound type 1 MMP (MT1-MMP) on cyst development using both in vitro 3 dimensional (3D) collagen gel culture and in vivo PCK rat model of PKD.
We found that collagen concentration is critical in controlling the morphogenesis of MDCK cells cultured in 3D gels. MDCK cells did not form 3D structures at collagen I concentrations lower than 1 mg/ml but began forming tubules when the concentration reaches 1 mg/ml. Significantly, these cells began to form cyst when collagen I concentration reached to 1.2 mg/ml, and the ratios of cyst to tubule structures increased as the collagen I concentration increased. These cells exclusively formed cyst structures at a collagen I concentration of 1.8 mg/ml or higher. Overexpression of MT1-MMP in MDCK cells significantly induced cyst growth in 3D collagen gel culture. Conversely, inhibition of MMPs activity with doxycycline, a FDA approved pan-MMPs inhibitor, dramatically slowed cyst growth. More importantly, the treatment of PCK rats with doxycycline significantly decreased renal tubule cell proliferation and markedly inhibited the cystic disease progression.
Our data suggest that increased collagen expression and MMP activity in PKD kidneys may induce cyst formation and expansion. Our findings also suggest that MMPs may serve as a therapeutic target for the treatment of human PKD.
PMCID: PMC3487993  PMID: 22963260
Collagen I; 3 dimensional (3D) collagen gel culture; Doxycycline; Matrix metalloproteinase; PCK rats; Polycystic kidney disease
3.  Inhibition of class II phosphoinositide 3-kinase γ expression by p185Bcr-Abl contributes to impaired chemotaxis and aberrant homing of leukemic cells 
Leukemia & lymphoma  2010;51(6):1098-1107.
Expression of p185Bcr-Abl in Ba/F3 cells inhibits chemotactic response of these cells to SDF1α. A mutant p185Bcr-Abl with deletion of amino acids from 176 to 426 (p185Δ176–426) is deficient in suppressing SDF1α-stimulated chemotaxis. Comparison of the gene expression profiles among parental Ba/F3 cells and the cells transformed by p185Bcr-Abl and p185Δ176–426 reveals that class II phosphoinositide 3-kinase γ (PI3KC2γ) expression is markedly down-regulated by p185Bcr-Abl but not p185Δ176–426. Furthermore, knockdown of PI3KC2γ expression in p185Δ176–426 cells is sufficient to suppress SDF1α-stimulated chemotaxis and to promote infiltration of these cells into liver. Together, these studies suggest that inhibition of PI3KC2γ expression may represent a mechanism by which Bcr-Abl suppresses SDF1α-induced chemotaxis and induces abnormal homing of leukemic cells.
PMCID: PMC2885034  PMID: 20536348
PI3KC2γ; p185Bcr-Abl; SDF-1α; chemotaxis
4.  Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells 
Carcinogenesis  2009;30(12):2109-2116.
Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo. We report here a novel function for Abi1 in the regulation of invadopodia formation and Src-inhibitor of differentiation protein 1 (Id1)-matrix metalloproteinase (MMP)-9 pathway in MDA-MB-231 human breast cancer cells. Abi1 is found in the invadopodia of MDA-MB-231 cells. Epigenetic silencing of the Abi1 gene by short hairpin RNA in MDA-MB-231 cells impaired the formation of invadopodia and resulted in downregulation of the Src activation and Id1/MMP-9 expression. The decreased invadopodia formation and MMP-9 expression correlate with a reduction in the ability of these cells to degrade extracellular matrix. Remarkably, the knockdown of Abi1 expression inhibited tumor cell proliferation and migration in vitro and slowed tumor growth in vivo. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer.
PMCID: PMC2792316  PMID: 19843640
6.  Abi1 gene silencing by short hairpin RNA impairs Bcr-Abl-induced cell adhesion and migration in vitro and leukemogenesis in vivo 
Carcinogenesis  2008;29(9):1717-1724.
Abl interactor (Abi) 1 was first identified as the downstream target of Abl tyrosine kinases and was found to be dysregulated in leukemic cells expressing oncogenic Bcr-Abl and v-Abl. Although the accumulating evidence supports a role of Abi1 in actin cytoskeleton remodeling and growth factor/receptor signaling, it is not clear how it contributes to Bcr-Abl-induced leukemogenesis. We show here that Abi1 gene silencing by short hairpin RNA attenuated the Bcr-Abl-induced abnormal actin remodeling, membrane-type 1 metalloproteinase clustering and inhibited cell adhesion and migration on fibronectin-coated surfaces. Although the knock down of Abi1 expression did not affect growth factor-independent growth of Bcr-Abl-transformed Ba/F3 cells in vitro, it impeded competitive expansion of these cells in non obese diabetic (NOD)/ severe combined immuno-deficiency (SCID) mice. Remarkably, the knock down of Abi1 expression in Bcr-Abl-transformed Ba/F3 cells impaired the leukemogenic potential of these cells in NOD/SCID mice. Abi1 contributes to Bcr-Abl-induced leukemogenesis in part through Src family kinases, as the knock down of Abi1 expression attenuates Bcr-Abl-stimulated activation of Lyn. Together, these data provide for the first time the direct evidence that supports a critical role of Abi1 pathway in the pathogenesis of Bcr-Abl-induced leukemia.
PMCID: PMC2527646  PMID: 18453543
7.  BCR-ABL Induces Abnormal Cytoskeleton Remodeling, β1 Integrin Clustering, and Increased Cell Adhesion to Fibronectin Through ABL Interactor 1 Pathway 
Journal of cell science  2007;120(Pt 8):1436-1446.
Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering, and cell adhesion. Expression of Bcr-Abl induces tyrosine phosphorylation of Abi1. This is accompanied by a subcellular translocation of Abi1/WAVE2 to a site adjacent to membrane, where an F-actin-enriched structure containing the adhesion molecules such as β1-integrin, paxillin, and vinculin is assembled. Bcr-Abl-induced membrane translocation of Abi1/WAVE2 requires direct interaction between Abi1 and Bcr-Abl, but is independent of phosphoinositide 3-kinase pathway. Formation of the F-actin-rich complex correlates with an increased cell adhesion to fibronectin. More importantly, disruption of the interaction between Bcr-Abl and Abi1 by mutations either in Bcr-Abl or Abi1 not only abolished tyrosine phosphorylation of Abi1 and membrane translocation of Abi1/WAVE2, but also inhibited Bcr-Abl-stimulated actin cytoskeleton remodeling, integrin clustering, and cell adhesion to fibronectin. Together, these data define Abi1/WAVE2 as a downstream pathway that contributes to Bcr-Abl-induced abnormalities of cytoskeletal and integrin function.
PMCID: PMC1950936  PMID: 17389688
Abi1; Bcr-Abl; WAVE2; actin cytoskeleton; β1-integrin; cell adhesion

Results 1-7 (7)