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Purpose: Nuclear factor nB (NF-nB) is an important transcription factor in various biological processes. Constitutive NF-nB activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear. Experimental Design: Constitutive NF-nB activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-nB activation, we established cancer cells with stable knockdown of InB kinase g (NF-nB essential modulator), which is the regulatory subunit of the InB kinase complex, by RNA interference. Cell growth and apoptosis were evaluated in wild-type cells (WT) and knocked-down cells (KD). Microarray and protein array analysis were also done. To determine involvement of angiogenesis, human umbilical vein endothelial cells were used. By s.c. transplantation of the cells into nude mice, tumor sizes, vascularity, and chemodrug sensitivity were analyzed. Results: Constitutive NF-nB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. Cell proliferation was not different between WT and KD in vitro, whereas apoptosis mediated by tumor necrosis factor-a and 5-fluorouracil were increased in KD. Several angiogenic chemokines were decreased in KD. Human umbilical vein endothelial cells incubated in WT supernatant showed more branch points than in KD, suggesting that constitutive NF-nB activation was involved in angiogenesis. Subcutaneous tumor expansion was suppressed to 23% in KD, and vessels were also decreased. By 5-fluoruracil treatment, tumor expansion was suppressed to a greater extent in KD (to 6%) than in WT (to 50%). Conclusion: NF-nB inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-nB activation.Colorectal cancer is the second leading cause of cancer-related death in industrialized nations (1). The development of colorectal cancer results from the sequential accumulation of activating mutations in oncogenes, such as ras, and mutations, truncations, or deletions in the coding sequences of several tumor suppressor genes, including p53 and adenomatous polyposis coli (APC; ref. 2).Over the last decade, there has been a great deal of progress in the development of new therapies for the treatment of colorectal cancer. The cytotoxic chemotherapy drug 5-fluorouracil (FU) was reformulated, and two new drugs, oxaliplatin and irinotecan, have been investigated as adjunctive therapies. In addition, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (VEGF; bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatments for metastatic colorectal carcinoma (3, 4). However, many cases show tolerance of such treatments (3, 4). Therefore, it is necessary to develop new approaches to replace or complement current therapies.Nuclear factor nB (NF-nB) transcription factors are key regulators of innate immune responses, inflammation, and cell survival (5), and are assembled...

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Inflammatory mediators such as TNF-α, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-κB. The aim of the present study was to investigate whether the NF-κB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IκB kinaseβ subunit (IKKβ) and inhibit NF-κB activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-κB activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-κB inhibition in both models. These results indicate that an IKKβ-targeted NF-κB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.

Epidemiologically, the association between chronic Helicobacter pylori infection and development of gastric cancer is well established. Although the possibility of preventing gastric cancer by eradicating H. pylori infection was recently investigated by several research groups, the results remain controversial. The aim of this study was to determine whether the eradication of H. pylori infection would reduce the incidence of gastric cancer. In total, 304 patients with persistent H. pylori infection and 404 patients with H. pylori infection eradicated were examined annually for gastric cancer by endoscopy. Over an average of 3.1 years for the first group and 3.2 years for the second group, 13 and 6 patients, respectively, were diagnosed as having new gastric cancer. The cumulative incidence of gastric cancer was statistically different between the groups (P=0.019; log-rank test). The hazard ratio of H. pylori eradication was 0.335 by Cox proportional hazards model (P=0.047). Differentiated gastric cancer was found in 11 patients in the persistent infection group and 3 patients in the eradicated group. The incidence of differentiated cancer was significantly different (P=0.017) between the groups, but not for undifferentiated cancer (P=0.847). The results of the current study suggest that the eradication of H. pylori infection reduces the incidence of gastric cancer.

c-Jun NH 2 -terminal kinase (JNK) links several cellular processes, including proliferation and survival, and is believed to be involved in carcinogenesis. However, the role of JNK in gastric tumorigenesis is unknown. Immunohistochemical analysis reveals that JNK is frequently activated in human gastric cancer tissue. We investigated whether JNK1, a major JNK isozyme, is involved in chemically induced gastric cancer development. Mice lacking JNK1 exhibited a marked decrease in gastric carcinogenesis induced by N-methyl-N-nitrosourea, relative to their wild-type counterparts. Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species. We also found that lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation. Taken together, JNK seems to be involved in both tumor initiation and promotion and may be an attractive target for the prevention of gastric carcinogenesis. [Cancer Res 2008;68(13):5031-9]

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M etastasis, the dissemination and growth of cancer cells in a secondary organ, is the leading cause of cancer mortality. 1 For example, the liver is a frequent metastatic site for melanoma and cancers of the colon and breast. Once liver metastases have developed, the natural course of the disease is associated with poor prognosis. Therefore, the development of new treatment modalities for metastatic liver cancer is urgently required. Tumor metastasis proceeds by way of a series of biological steps that move tumor cells from the primary organ to a distant location. During this process, tumor metastasis is governed by a variety of genetic and epigenetic factors. 2 Nuclear factor kappaB (NF-B) transcription factors are critical regulators of genes involved in inflammation and the suppression of apoptosis. 3 In resting cells, NF-B is maintained inactive in the cytoplasm by I B inhibitors, which are rapidly degraded in response to stimuli such as tumor necrosis factor alpha (TNF-␣) and bacterial lipopolysaccharide (LPS), resulting in NF-B activation and