Atherosclerosis is now generally accepted as a chronic inflammatory condition. The transcription factor NF-κB is a key regulator of inflammation, immune responses, cell survival, and cell proliferation. To investigate the role of NF-κB activation in macrophages during atherogenesis, we used LDL receptor-deficient mice with a macrophage-restricted deletion of IκB kinase 2 (IKK2), which is essential for NF-κB activation by proinflammatory signals. These mice showed increased atherosclerosis as quantified by lesion area measurements. In addition, the lesions were more advanced and showed more necrosis and increased cell number in early lesions. Southern blotting revealed that deletion of IKK2 was approximately 65% in macrophages, coinciding with a reduction of 50% in NF-κB activation, as compared with controls. In both groups, the expression of differentiation markers, uptake of bacteria, and endocytosis of modified LDL was similar. Upon stimulation with LPS, production of TNF was reduced by approximately 50% in IKK2-deleted macrophages. Interestingly, we also found a major reduction in the anti-inflammatory cytokine IL-10. Our data show that inhibition of the NF-κB pathway in macrophages leads to more severe atherosclerosis in mice, possibly by affecting the proand anti-inflammatory balance that controls the development of atherosclerosis.

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Background: Gain of a large segment of chromosome 20q is associated with progression of colorectal adenomas into carcinomas, implying that multiple genes on the 20q amplicon drive carcinogenesis. Candidate driver genes are expected to be expressed at mRNA and protein levels that correlate with the 20q amplicon DNA copy number status, while functionally affecting one or several cancer-related processes. Integration of CGH profiles with mRNA profiles of a series of colorectal tumors revealed thirty-two candidate genes whose DNA copy number status correlated with mRNA expression levels. Aim: To functionally analyse the effects of the candidate oncogenes on cancer-related processes by downregulation using siRNA strategies. Results: Downmodulation of TPX2 (20q11.2) and AURKA (20q13.2) mRNA expression in CRC cell lines with 20q gain affected cell viability, anchorage-independent growth, and invasion. Moreover, immunohistochemical evaluation demonstrated a significant correlation between their protein levels and 20q DNA copy number status in a series of colorectal adenomas and carcinomas. Conclusion: These data demonstrate that at least two genes located on distinct regions of chromosome 20q promote colorectal adenoma-to-carcinoma progression and indicate that TPX2, like AURKA, is a promising target for anti-cancer drug development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3042. doi:10.1158/1538-7445.AM2011-3042

Inbred strains of mice exhibit large differences in their susceptibility to various complex quantitative genetic traits, among which is the susceptibility to lung cancer. These differences are caused by the combined effects of multiple quantitative trait loci (QTLs). Due to their multiplicity, it is relatively difficult and laborious to study the effects of individual QTLs. To dissect complex genetic traits the authors make use of recombinant congenic strains (RCS), a system of mouse inbred strains in which the genetic complexity is reduced. The susceptibility to lung cancer is studied by using the series of O20-congenic-B10.O20 (OcB) RC strains. They are derived from the parental background strain O20 and the parental donor strain B10.O20, two mouse inbred strains that differ from each other in both quantitative and qualitative aspects of lung tumorigenesis. This study describes the segregation of lung tumor number, size, and histology among the OcB RC strains, and indicates that these traits are influenced by multiple interacting QTLs with considerable individual effects. The results suggest that some of the susceptibility loci to lung cancer affect the susceptibility to other types of cancer as well, possibly by functioning systematically.