Comparative clinicopathological and immunohistochemical study of ras and p53 in flat and polypoid type colorectal tumours.

Yukawa, Masahiko; Fujimori, Takahiro; Maeda, Satoko; Tabuchi, Maiko; Nagasako, K

doi:10.1136/gut.35.9.1258

Cited by 65 publications

(38 citation statements)

References 18 publications

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“…In order to assess and grade intensity and distribution of immunoreactivity in the colonic epithelium, a scoring method that has been previously described (Yukawa et al, 1994) was used. The distribution was scored according to the number of positive cells: none (not stained), 0; focal (o1/3 of cells stained), 1; multifocal (1/3 -2/3 of cells stained), 2; and diffuse (42/3 stained), 3.…”

Section: Immunohistochemical Evaluationmentioning

confidence: 99%

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

et al. 2003

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Cyclooxygenase-2 (COX-2) is selectively overexpressed in colorectal tumours. The mechanism of COX-2 induction is not fully understood, but requires de novo messenger RNA and protein synthesis, indicating regulation at the transcriptional level. Sequence analysis of the 5 0 -flanking region of the COX-2 gene shows two nuclear factor-kB (NF-kB) sites. Inhibition of this protein in model cell culture systems attenuates COX-2 expression and implies that NF-kB plays an important role in COX-2 induction. We measured COX-2, NF-kB and IkB kinase a (IKKa) protein expression in matched colonic biopsy samples comprising both nontumour and adjacent tumour tissue from 32 colorectal cancer patients using immunohistochemistry. There was none or very little expression of COX-2, NF-kB and IKKa in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (Po0.05, Wilcoxon's signed rank test) in adjacent cancerous cells. Moreover, all three proteins were found to be coexpressed in the neoplastic epithelium, with the expression of COX-2 and NF-kB highly correlated (Pearson's correlation, Po0.005). There was no apparent correlation between enhanced COX-2, NF-kB or IKKa expression and tumour Dukes' stages. Our results are compatible with the hypothesis that IKKa and NF-kB are involved in COX-2 induction in these tumours and the lack of association between COX-2 expression and severity of disease as measured by Dukes' stage is consistent with the proposal that COX-2 expression is an early postinitiation event.

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Section: Immunohistochemical Evaluationmentioning

confidence: 99%

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

et al. 2003

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“…The frequency of K-ras mutations is less than that of conventional sporadic colorectal tumors mostly derived from an exophytic adenoma-carcinoma sequence Minamoto et al, 1994;Olschwang et al, 1998). Also, flat tumors frequently demonstrate early inactivation of p53 with concomitant allelic loss of 17p (Yukawa et al, 1994;Rubio and Rodensjo, 1996;Mueller et al, 1998). Through microdissection and loss of heterozygosity (LOH) analysis, we identified patterns of genetic progression and/or divergence in these flat colorectal neoplastic foci, with some foci evolving into an invasive form (Fujii et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

et al. 2004

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Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.

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“…To assess and grade intensity and distribution of immunoreactivity in the colorectal stromal and epithelial cells, a scoring method, which has been described earlier was used (Yukawa et al, 1994). The distribution was scored according to the number of positive cells; none (not stained), 0; focal (o1/3 of cells stained), 1; multi-focal (1/3 -2/3 of cells stained), 2; and diffuse (42/3 stained), 3.…”

Section: Immunohistochemical Evaluationmentioning

confidence: 99%

Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

et al. 2009

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BACKGROUND: Cyclooxygenase-2 (COX-2) is selectively over-expressed in colorectal tumours. The mechanism of COX-2 induction in these tumours is not fully understood, although evidence suggests a possible link between nuclear factor (NF)-kB and COX-2. We hypothesised an association between COX-2 expression and NF-kB-p65, NF-kB-p50 and IkB-kinase-a (IKKa) in both epithelial and stromal cells in human colorectal cancer. METHODS: Using immunohistochemistry, we measured COX-2, NF-kB-p65, NF-kB-p65 nuclear localisation sequence (NLS), NF-kBp50, NF-kB-p50 NLS and IKKa protein expression in matched colorectal biopsy samples comprising both non-tumour and adjacent tumour tissue from 32 patients with colorectal cancer. RESULTS: We have shown that stromal cells of malignant and surrounding normal colorectal tissue express COX-2. In all cell types of malignant tissue, and in vascular endothelial cells (VECs) of neighbouring normal tissue, COX-2 expression was strongly associated with NF-kB-p65 expression (Pearson's correlation, P ¼ 0.019 for macrophages, P ¼ 0.001 for VECs, P ¼ 0.002 for fibroblasts (malignant tissue), and P ¼ 0.011 for VECs (non-malignant tissue)) but not NF-kB-p50 or IKKa. CONCLUSIONS: These data suggest that in these cells COX-2 induction may be mediated through activation of the canonical NF-kB pathway. Finally, the lack of association between COX-2, NF-kB-p65 or IKKa in stromal cells with the clinical severity of colorectal cancer as determined by Duke's stage, suggests that COX-2, NF-kB-p65 and IKKa expression are possibly early post-initiation events, which could be involved in tumour progression.

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Comparative clinicopathological and immunohistochemical study of ras and p53 in flat and polypoid type colorectal tumours.

Cited by 65 publications

References 18 publications

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

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