Abstract
N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-kappaB (NF-kappaB) signaling attenuation through marked decreases in inhibitor of kappaB kinase (IKK) beta expression and IkappaBalpha phosphorylation. Decreased IKKbeta expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-kappaB motif. The introduction of an exogenous IKKbeta gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity alpha/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IkappaBalpha in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-kappaB signaling.
Highlights
N-myc downstream regulated gene 1 (NDRG1)/Cap43 is one of the metastasis suppressor genes [1], and expression of NDRG1/Cap43 is regulated by oncogenes (N-myc and C-myc) and tumor suppressor genes (p53, VHL, and PTEN; ref. 2)
We further showed that expression of NDRG1/Cap43 is associated with a marked decrease of tumor angiogenesis in mice bearing human pancreatic cancer xenografts and that NDRG1/Cap43 markedly suppresses the expression of matrix metalloproteinase-9, vascular endothelial growth factor (VEGF), and interleukin (IL)-8/CXCL8
Because our previous study showed that NDRG1/Cap43 overexpression in pancreatic cancer cells reduced the expression of angiogenesis-related factors such as VEGF-A and IL-8/CXCL8 [5], we selected these genes, the expression of which showed a decrease of ∼0.7 (Supplementary Table S2)
Summary
N-myc downstream regulated gene 1 (NDRG1)/Cap is one of the metastasis suppressor genes [1], and expression of NDRG1/Cap is regulated by oncogenes (N-myc and C-myc) and tumor suppressor genes (p53, VHL, and PTEN; ref. 2). Expression of NDRG1/Cap protein is often elevated in many types of human tumors. Expression of NDRG1/Cap depends on tumor type and differentiation status [2]. We previously identified NDRG1/Cap as one of the nine genes that are highly expressed in cancerous regions of human renal cell carcinoma [13], and its expression is closely associated with the VHL oncosuppressor gene [14]. We further showed that expression of NDRG1/Cap is associated with a marked decrease of tumor angiogenesis in mice bearing human pancreatic cancer xenografts and that NDRG1/Cap markedly suppresses the expression of matrix metalloproteinase-9, vascular endothelial growth factor (VEGF), and interleukin (IL)-8/CXCL8. Expression of NDRG1/Cap has been associated with decreased microvessel density (MVD) and differentiation or depth of invasion in cancer cells in patients with pancreatic cancer [5]
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