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Hirofumi Ueda,
Hiroyuki Tanaka,
Kazuhito Ichikawa,
Michio Itabashi,
Shingo Kameoka, Shigehiko Fujii,
Natsuko Saito,
Ryusuke Kimura,
Yosuke Shida,
Yukari Fujimori,
Shinichirou Ohtake,
Shigeki Tomita,
Johji Imura,
Yoshikazu Yasuda,
Nobuhiko Tanigawa,
Kazuhisa Uchiyama,
Takahiro Fujimori
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ABSTRACT: PURPOSE: Making a clinicopathological diagnosis of dysplasia is crucial. We herein assess the significance of the DNA methyltransferase 3b (DNMT3b) expression as a diagnostic marker of ulcerative colitis (UC)-associated neoplasia. METHODS: Thirty-one patients with long-standing and extensive UC were included in this study. The expression of DNMT3b in non-neoplastic rectal epithelium (non-dysplasia in 31 patients) and colorectal neoplasia (dysplasia in 43 patients and invasive cancer in 34 patients) was determined using immunohistochemistry. The presence of immunoreactive DNMT3b was assessed in the areas with the highest density of cells with positively staining nuclei. DNMT3b was expressed as the percentage of positive cells relative to the total number of cells counted under high power magnification. RESULTS: The DNMT3b expression in neoplastic rectal epithelium (0.76, range 0.59-0.84) was increased compared to that observed in non-neoplastic epithelium (0.32, range 0.18-0.67, P < 0.001). A ROC curve analysis confirmed 0.68 to be the best diagnostic cut-off value for the DNMT3b expression in neoplastic epithelium (area under the curve = 0.810). The sensitivity of the diagnostic test was 66.2 %, the specificity was 86.7 %, the positive predictive value was 95.7 % and the negative predictive value was 36.1 %. The positive likelihood ratio was 4.98 and the negative likelihood ratio was 0.20. The accuracy was 69.9 %. CONCLUSIONS: An immunohistochemical analysis of the DNMT3b expression was associated with significant improvements in the discrimination of UC-associated neoplastic lesions.
Surgery Today 01/2013; · 1.22 Impact Factor
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Hirokazu Fukui,
Akira Sekikawa,
Hiroyuki Tanaka,
Yukari Fujimori,
Yoshinori Katake, Shigehiko Fujii,
Kazuhito Ichikawa,
Shigeki Tomita,
Johji Imura,
Tsutomu Chiba,
Takahiro Fujimori
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ABSTRACT: Interleukin (IL)-22 is a recently identified cytokine that is suggested to play pivotal roles in various inflammatory diseases. Although the IL-22 receptor 1 (IL-22R1) is restrictively expressed in epithelial cells in the colon, the role of IL-22 in colonic diseases still remains unclear. In this study microarray analyses revealed that deleted in malignant brain tumors 1 (DMBT1) is a novel upregulated gene in IL-22-stimulated colon cancer cells. Therefore, we investigated the involvement of DMBT1 and IL-22 in ulcerative colitis (UC) tissues and examined the mechanism regulating the expression of DMBT1 in response to IL-22 stimulation.
Changes of gene expression in IL-22-stimulated SW403 cells were investigated by microarray analyses. The effects of IL-22 on DMBT1 expression were examined in SW403 cells using a small interfering RNA (si)RNA for STAT3 or inhibitors for MEK, PI3K, and nuclear factor kappa B (NF-κB). The element responsible for IL-22-induced DMBT1 promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay (EMSA). Expression of IL-22, IL-22R1, and DMBT1 in UC tissues was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry.
IL-22 treatment enhanced the expression of DMBT1 through STAT3 tyrosine phosphorylation and NF-κB activation in colon cancer cells. The IL-22-responsive element was located between -187 and -179 in the DMBT1 promoter region. In the UC mucosa the levels of DMBT1 and IL-22 mRNA expression were significantly enhanced and positively correlated, the numbers of IL-22-positive lymphocytes were increased, and the expression of IL-22R1 and DMBT1 was enhanced in the inflamed epithelium.
The IL-22/DMBT1 axis may play a pivotal role in the pathophysiology of UC.
Inflammatory Bowel Diseases 05/2011; 17(5):1177-88. · 4.86 Impact Factor
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Hiroyuki Tanaka,
Hirokazu Fukui, Shigehiko Fujii,
Akira Sekikawa,
Hidetsugu Yamagishi,
Kazuhito Ichikawa,
Shigeki Tomita,
Johji Imura,
Yoshikazu Yasuda,
Tsutomu Chiba,
Takahiro Fujimori
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ABSTRACT: The regenerating gene (REG)Iα has been identified by microarray analysis as a gene that is distinctly overexpressed in ulcerative colitis (UC), and its protein product is suggested to play a pivotal role in the development of UC-associated carcinoma. In the present study, we investigated the significance of REG Iα expression as a diagnostic marker of UC-associated neoplasia.
Tissue samples were obtained from colectomy specimens from 31 patients with long-standing UC (mean disease duration 17.2 years, range 5-29). The lesions were evaluated according to the International Classification for Dysplasia in Inflammatory Bowel Diseases, and the sections were examined using immunohistochemistry for REG Iα and p53.
In the 'regenerating atypia' group, REG Iα immunoreactivity was restricted to the lower third of the UC mucosa (grade 1). Lesions classified as 'indefinite for dysplasia' also showed predominantly basal-type staining for REG Iα. However, in 'low-grade dysplasia' and 'high-grade dysplasia' lesions, the localization of REG Iα immunoreactivity expanded to the middle (grade 2) and upper (grade 3) third of the UC mucosa, respectively. The REG Iα immunostaining pattern differed significantly (p < 0.0001) between non-neoplastic and neoplastic lesions, and was significantly (p < 0.0001) associated with p53 overexpression.
Immunohistochemical analysis of REG Iα expression is useful for differential diagnosis of non-neoplastic and neoplastic lesions in UC tissues.
Digestion 01/2011; 83(3):204-9. · 2.05 Impact Factor
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Akira Sekikawa,
Hirokazu Fukui,
Katsumasa Suzuki,
Toyohiko Karibe, Shigehiko Fujii,
Kazuhito Ichikawa,
Shigeki Tomita,
Johji Imura,
Keiko Shiratori,
Tsutomu Chiba,
Takahiro Fujimori
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ABSTRACT: The Regenerating gene (REG) Ialpha protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Ialpha axis and examined the mechanism of regulation of REG Ialpha expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Ialpha in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Ialpha protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Ialpha promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Ialpha was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Ialpha and IL-22 mRNA expression were strongly correlated, and the distributions of REG Ialpha- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Ialpha protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between -142 and -134 in the REG Ialpha promoter region. REG Ialpha protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.
Laboratory Investigation 03/2010; 90(3):496-505. · 3.64 Impact Factor
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ABSTRACT: To clarify the possible significance of increased expression of DNA methyltransferase (DNMT)-1 in the tumorigenesis of colorectal neoplasia in ulcerative colitis (UC) and to clarify whether analysis of DNMT1 expression in non-neoplastic epithelium can contribute to the prediction of increased risk for UC-associated neoplasia.
Sixty-two patients with long-standing and extensive UC were included in this study: 31 with colorectal neoplasia (dysplasia in 11 and invasive cancer in 20) and 31 without. Immunohistochemical analysis and quantitative RT-PCR were performed to determine the expression of DNMT1 in rectal epithelium of UC patients without neoplasia, and in non-neoplastic rectal epithelium and colorectal neoplasia of UC patients with neoplasia.
The immunoreactive DNMT1 expression gradually increased from rectal epithelium of UC patients without neoplasia (0.13 +/- 0.07) to non-neoplastic rectal epithelium of UC patients with neoplasia (0.32 +/- 0.12, p < 0.001), and to colorectal neoplasia (0.54 +/- 0.20, p < 0.001). Among 31 neoplasias, there was no difference in the immunoreactive DNMT1 expressions between dysplasia and invasive cancer (0.47 +/- 0.52 vs. 0.58 +/- 0.63). The expression level of DNMT1 mRNA tended to increase gradually from rectal epithelium of UC patients without neoplasia (0.53 +/- 0.34) to non-neoplastic rectal epithelium of UC patients with neoplasia (0.88 +/- 0.57, p = 0.06), and to colorectal neoplasia (1.38 +/- 0.64, p = 0.07).
Increased expression of DNMT1 in non-neoplastic epithelium may precede or be a relatively early event in UC-associated tumorigenesis, and may help predict the risk of colorectal neoplasia in UC.
Digestion 01/2010; 82(3):179-86. · 2.05 Impact Factor
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Hidetsugu Yamagishi,
Hirokazu Fukui,
Akira Sekikawa,
Tokuyuki Kono, Shigehiko Fujii,
Kazuhito Ichikawa,
Shigeki Tomita,
Johji Imura,
Hideyuki Hiraishi,
Tsutomu Chiba,
Takahiro Fujimori
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ABSTRACT: Regenerating gene family members 1 (REG Ialpha) and 4 (REG IV) are overexpressed in a subset of gastric cancers. However, comparative characterization of the expression of these family proteins has remained unclear. Therefore, we aimed to elucidate not only the association between REG protein expression and mucin phenotype but also their significance as a prognostic marker for patients with gastric cancer. The expression of REG Ialpha, REG IV, CDX2, MUC2, and MUC5AC in gastric cancer tissues was examined by immunohistochemistry. The relationship between REG protein expression and clinicopathological parameters or mucin phenotype was then analyzed. REG Ialpha and REG IV expression was positive in 33 (52%) and 31 (49%) of 63 gastric cancers examined, respectively. REG Ialpha expression was significantly related to venous invasion and tumor stage, whereas REG IV expression showed no relationship to clinicopathological features. With regard to mucin phenotype, REG IV expression was significantly correlated with MUC2 and CDX2 expression, suggesting an association with the intestinal mucin phenotype of gastric cancer. On the other hand, REG Ialpha expression had no correlation with MUC2, CDX2, or MUC5AC in gastric cancer tissues. Expression of REG Ialpha but not REG IV was an independent predictor of poor outcome in patients with gastric cancer. In addition, patients with gastric cancer negative for both REG Ialpha and REG IV expression had a significantly better outcome than patients positive for either REG Ialpha or REG IV. Profiling of REG protein expression is useful to for prognostication of patients with gastric cancer.
Modern Pathology 04/2009; 22(7):906-13. · 4.79 Impact Factor
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ABSTRACT: This review consists of 6 sections: (1) pathological diversity of cancer and the correlation between 'zokushutsu' (budding/sprouting) and lymph node metastasis; (2) genetic analysis and metastasis in the gastrointestinal tract; (3) conditions requiring resection after endoscopic treatment; (4) improvement of methods used to measure depth of submucosal invasion in the Ip type; (5) Japanese morphological classification of colorectal neoplastic lesions in terms of the clinical pathology and genetics of laterally spreading tumors; (6) villous tumors.
Digestion 02/2009; 79 Suppl 1:40-51. · 2.05 Impact Factor
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ABSTRACT: Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutations in the immunoglobulin gene. We recently revealed that ectopic AID expression serves as a link between the cellular editing machinery and high mutation frequencies, leading to human cancer development. In the current study, we investigated whether AID might contribute to the development of colitis-associated colorectal cancers.
The expression and regulation of AID in association with proinflammatory cytokine stimulation were investigated in cultured colonic cells. Genotoxic activity of AID in colonic cells was analyzed using retroviral system. Immunohistochemistry for AID was carried out on various human colonic tissues specimens.
Tumor necrosis factor-alpha induced aberrant AID expression via IkappaB kinase-dependent nuclear factor (NF)-kappaB-signaling pathways in human colonic epithelial cells. Moreover, AID expression was also induced in response to the T helper cell 2-driven cytokines interleukin-4 and interleukin-13, which are activated in human inflammatory bowel disease. Aberrant activation of AID in colonic cells preferentially induced genetic mutations in the TP53 gene, whereas there were no nucleotide alterations of the APC gene. Immunohistochemistry revealed enhanced expression of endogenous AID protein not only in the inflamed colonic mucosa of ulcerative colitis patients but also in tumor lesions of colitis-associated colorectal cancers.
Our findings indicate that proinflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells is a genotoxic factor linking inflammation, somatic mutations, and colorectal cancer development.
Gastroenterology 07/2008; 135(3):889-98, 898.e1-3. · 11.68 Impact Factor
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Kenichiroh Mukawa, Shigehiko Fujii,
Keiichi Tominaga,
Naoto Yoshitake,
Akihito Abe,
Tokuyuki Kono,
Akira Sekikawa,
Hirokazu Fukui,
Kazuhito Ichikawa,
Shigeki Tomita,
Johji Imura,
Yuko Ono,
Motoo Shinoda,
Hideyuki Hiraishi,
Takahiro Fujimori
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ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are representative agents for the chemoprevention of sporadic colorectal neoplasia. However, few reports have described the chemopreventive effects of such agents on colitis-associated tumorigenesis. To clarify whether treatment with the COX-2 inhibitor may reduce the risk of colitis-associated neoplasia, we investigated the effect of one such agent, etodolac, on tumorigenesis in the colitis-associated neoplasia model using p53-deficient mice treated with dextran sulfate sodium (DSS). The p53-/- mice were divided into four groups: i) treatment with DSS + etodolac, then after two cycles of DSS, the mice were given distilled water for 84 days. In addition, etodolac was administered three times a week at a dose of 10 mg/kg body weight throughout the experiment. ii) Treatment with two cycles of DSS only, followed by distilled water for 84 days. iii) Treatment with etodolac alone. iv) Distilled water alone was administered to the control group. The incidence of mice with neoplasia was 82.4% in the DSS + etodolac group and 100% in the DSS-alone group. No neoplasia was observed in the etodolac-alone and control groups. The mean (+/- SEM) number of total neoplasias per mouse was 1.29+/-0.2 in the DSS + etodolac group and 3.0+/-0.52 in the DSS-alone group, the inter-group difference being significant (p<0.01). There was no significant difference in the inflammation score between these two groups. These results showed that treatment with etodolac significantly reduced the occurrence of neoplasia, suggesting that this COX-2 inhibitor has chemopreventive activity against colitis-associated tumorigenesis.
Oncology Reports 03/2008; 19(2):393-9. · 1.84 Impact Factor
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ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) Ialpha protein, an interleukin (IL)-6-inducible gene, is suggested to be involved in the gastritis-gastric cancer sequence. We investigated the involvement of IL-6/STAT3 signaling in REG Ialpha protein expression and examined whether REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG Ialpha protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG Ialpha promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG Ialpha protein were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and REG Ialpha protein. IL-6 treatment enhanced the expression of REG Ialpha protein through STAT3 activation in gastric cancer cells. The IL-6-responsive element was determined to lie in the sequence from -142 to -134 of the REG Ialpha promoter region. REG Ialpha protein mediated the anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL expression. The expression of REG Ialpha protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG Ialpha protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.
Carcinogenesis 02/2008; 29(1):76-83. · 5.70 Impact Factor
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ABSTRACT: The incidence of colorectal neoplasia has been increasing among patients with long-standing and extensive ulcerative colitis (UC), and therefore surveillance colonoscopy has been widely recommended. However, because UC-associated neoplasia is often difficult to detect endoscopically and to discriminate from inflammatory regenerative epithelium histologically, the efficacy of current surveillance remains unsatisfactory. In order to overcome these difficulties, adjunctive modalities for diagnosing UC-associated neoplasia, chromo- and magnifying endoscopy for endoscopic diagnosis and analysis of p53 alteration for histological diagnosis have been introduced. Furthermore, if it were possible to differentiate UC patients with long-standing and extensive colitis into subgroups with a high and a low risk of neoplasia, it would enable physicians to conduct more intensive surveillance with these modalities for patients at higher risk. Several molecular alterations of nonneoplastic epithelium in UC patients with neoplasia may be promising as markers for identifying individuals with UC at increased risk of neoplasia. We evaluated estrogen receptor (ER) methylation of nonneoplastic colorectal epithelium to clarify whether this epigenetic alteration can contribute to the prediction of increased neoplasia risk in UC patients and demonstrated that the ER methylation level in nonneoplastic epithelium was higher throughout the colorectum in patients with neoplasia than in those without. These results suggest that analysis of ER gene methylation may be potentially useful for identifying individuals at increased risk of neoplasia among patients with long-standing and extensive UC.
Digestion 02/2008; 77 Suppl 1:2-12. · 2.05 Impact Factor
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Naoto Yoshitake,
Hirokazu Fukui, Shigehiko Fujii,
Kenichiroh Mukawa,
Keiichi Tominaga,
Akira Sekikawa,
Shigeki Tomita,
Kazuhito Ichikawa,
Johji Imura,
Kiyokazu Nakajima,
Riichiro Nezu,
Yukinori Yamada,
Harumasa Yoshihara,
Hideyuki Hiraishi,
Takahiro Fujimori
Inflammatory Bowel Diseases 11/2007; 13(10):1319-21. · 4.86 Impact Factor
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Akihito Abe,
Hirokazu Fukui, Shigehiko Fujii,
Mikio Fujita,
Kenichiroh Mukawa,
Kazuhito Ichikawa,
Shigeki Tomita,
Yuko Ono,
Yasuo Imai,
Johji Imura,
Keiichi Kubota,
Takahiro Fujimori
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ABSTRACT: Although patients with early colorectal cancer invading the submucosa (CRC-sm) may be treated with endoscopic mucosal resection alone, they generally undergo additional surgery because of the risk of lymph node metastasis. The aims of the present study were to examine the roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in tumor vascularization and to investigate whether COX-2 and VEGF expression and tumor vascularity are useful markers for predicting lymph node metastasis in CRC-sm.
Twenty-seven resected specimens of CRC-sm with lymph node dissection were examined, and expression of COX-2 and VEGF was evaluated immunohistochemically and scored. Microvessel density (MVD) in CRC-sm tissues was estimated using a Macscope system after CD34 immunostaining. The relationships among clinicopathological parameters, COX-2 and VEGF expression, and MVD in CRC-sm tissues were then analyzed.
Scores for COX-2, VEGF and MVD were all significantly higher in patients with CRC-sm with lymphatic invasion or lymph node metastasis. COX-2 score (P < 0.0001) and VEGF score (P = 0.035) were significantly correlated with MVD in CRC-sm tissues. In addition, COX-2 score was significantly correlated with VEGF score in the CRC-sm specimens examined.
Both COX-2 and VEGF are involved in tumor vascularization in CRC-sm. COX-2 expression, VEGF expression, and MVD are possible markers for predicting lymph node metastasis in patients with CRC-sm, and use of COX-2 expression may be clinically practical.
Journal of Gastroenterology and Hepatology 08/2007; 22(7):1071-7. · 2.87 Impact Factor
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ABSTRACT: The regenerating gene (REG) IV gene was isolated from a cDNA library of ulcerative colitis (UC) tissues. However, its role in the pathophysiology of UC and subsequent development of colitic cancer is still unclear. We investigated the expression of the REG IV gene in UC and colitic cancer tissues and examined whether cytokines or growth factors are responsible for REG IV gene expression and whether REG IV gene induction affects cell growth and apoptosis in colon cancer cells. The expressions of REG IV and growth factor genes in UC tissues were analyzed by real time reverse transcription-polymerase chain reaction. The effects of cytokines and growth factors on REG IV gene expression were examined in SW403 cells by Northern blot analysis. The effects of REG IV gene induction on cell growth and H(2)O(2)-induced apoptosis were examined in DLD-1 cells by MTT and TUNEL assays, respectively. REG IV mRNA was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG IV mRNA expression was correlated with that of basic fibroblast growth factor (bFGF) as well as hepatocyte growth factor (HGF) mRNA expression in UC tissues. The REG IV gene expression in SW403 colon cancer cells was enhanced by stimulation with transforming growth factor-alpha, epidermal growth factor, bFGF, and HGF. REG IV gene induction promoted cell growth and conferred resistance to H(2)O(2)-induced apoptosis in DLD-1 cells. The REG IV gene is inducible by growth factors and may function as a growth promoting and/or an antiapoptotic factor in the pathophysiology of UC.
Laboratory Investigation 04/2007; 87(3):304-14. · 3.64 Impact Factor
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Naoto Yoshitake, Shigehiko Fujii,
Kenichiroh Mukawa,
Keiichi Tominaga,
Hirokazu Fukui,
Kazuhito Ichikawa,
Shigeki Tomita,
Yuko Ono,
Yasuo Imai,
Akira Terano,
Hideyuki Hiraishi,
Takahiro Fujimori
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ABSTRACT: Genetic alterations and their association with clinicopathological features in colorectal mucinous carcinoma (MC) remain unknown. In particular, little is known about the mutational status of the BRAF gene, which is activated by oncogenic Ras. This study aimed to evaluate the status of BRAF together with K-ras, p53 and mismatch-repair deficiency to clarify their association with tumorigenesis of colorectal MC. BRAF and K-ras mutations were determined in 43 colorectal MCs by direct sequencing. p53 alteration was investigated immunohistochemically. The status of mismatch-repair deficiency was assessed by microsatellite analyses and immunohistochemistry for hMLH1. We also examined the association between these molecular alterations and clinicopathological features including histological configuration. BRAF mutation was detected in 4 (9.3%) tumors and was located at codon 599 of exon 15 in all cases. K-ras mutation was detected in 13 tumors (30.2%). No BRAF and K-ras mutations were identified simultaneously in the same tumor. The incidence of mismatch-repair deficiency tended to be higher in MC with BRAF mutation than without. In terms of histological configuration, we classified the cases according to growth type by tumor edge morphology. All MCs with BRAF mutation and 9 of 13 MCs (69.2%) with K-ras mutation were classified as polypoid type. BRAF and K-ras mutation did not affect patient prognosis, but non polypoid type was significantly more aggressive than polypoid type. Our findings indicate that BRAF mutation plays an important role in the tumorigenesis of colorectal MC and in tumor edge morphology, similar to K-ras mutation.
Oncology Reports 02/2007; 17(1):9-15. · 1.84 Impact Factor
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The Lancet 12/2006; 368(9549):1842. · 38.28 Impact Factor
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Keiichi Tominaga, Shigehiko Fujii,
Kenichiroh Mukawa,
Mikio Fujita,
Kazuhito Ichikawa,
Shigeki Tomita,
Yasuo Imai,
Kazunari Kanke,
Yuko Ono,
Akira Terano,
Hideyuki Hiraishi,
Takahiro Fujimori
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ABSTRACT: The incidence of colorectal neoplasia has increased among patients with longstanding and extensive ulcerative colitis (UC). Therefore, surveillance colonoscopy has been widely recommended. However, there is controversy about the impact of cancer surveillance, and ways to improve its effectiveness are being sought. The estrogen receptor (ER) gene shows age-related methylation in the colorectal epithelium and is frequently methylated in colorectal neoplasia, suggesting that ER methylation occurs early in the process of colorectal tumorigenesis.
To clarify whether methylation analysis of the ER gene in nonneoplastic epithelium can help predict an increased risk for UC-associated neoplasia, a total of 105 nonneoplastic colorectal epithelia from 18 patients with longstanding and extensive UC, including 8 patients with neoplasia and 10 patients without neoplasia, were analyzed. In all patients, multiple samples were taken from six regions of the colorectum. The combined bisulfite restriction analysis method was used to determine the methylation status of the ER gene.
The mean methylation level of the ER gene was 25.4% in the nonneoplastic epithelia from UC patients with neoplasia, whereas it was only 4.0% in those without neoplasia (P<0.001). The methylation level of the ER gene in UC patients with neoplasia was significantly higher than in UC patients without neoplasia throughout the colorectum except for the cecum. In UC patients with neoplasia, the mean ER methylation level in the distal colon (36.1%) was significantly higher than in the proximal colon (14.6%; P<0.001).
These results suggest that the analysis of ER gene methylation in nonneoplastic colorectal epithelium could have the potential to be a useful adjunct for identifying individuals with longstanding and extensive UC who are at increased risk of neoplasia and contribute to more effective cancer surveillance.
Clinical Cancer Research 01/2006; 11(24 Pt 1):8880-5. · 7.74 Impact Factor
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Kenichiroh Mukawa, Shigehiko Fujii,
Jun Takeda,
Kazuaki Kitajima,
Keiichi Tominaga,
Yoko Chibana,
Mikio Fujita,
Kazuhito Ichikawa,
Shigeki Tomita,
Yuko Ono,
Johji Imura,
Hitoshi Kawamata,
Tsutomu Chiba,
Hideyuki Hiraishi,
Akira Terano,
Takahiro Fujimori
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ABSTRACT: Recent advances in colonoscopic techniques have led to the increased detection of, and interest in, superficial type colorectal tumors, and a new category, the 'laterally spreading tumor (LST)', has been proposed. However, the characteristics of the genetic alterations in these LSTs have not yet been fully determined. We therefore classified LSTs as LST-granular (LST-G) or LST-non-granular (LST-NG), according to their macroscopic appearance, and examined the genetic alterations in these two tumor groups compared with those in protruded type tumors.
We obtained a total of 62 colorectal tumors, including 26 protruded type, 17 LST-G and 19 LST-NG, from specimens resected surgically or endoscopically. We examined K-ras codon 12 mutations by using the polymerase chain reaction-restriction fragment length polymorphism method and by fluorescence direct sequencing. We also performed immunohistochemistry to analyze cyclooxygenase (COX)-2 and gastrin abnormalities.
The incidence of K-ras mutation was 50.0% in protruded type tumors, 76.5% in LST-G, and 26.3% in LST-NG. The frequencies of COX-2 overexpression were 73.1, 88.2, and 31.6%, respectively, and those of gastrin overexpression were 61.5, 82.4, and 26.3%, respectively. Therefore, LST-G is similar to protruded type tumors in that the incidence of K-ras mutation and the frequencies of COX-2 and gastrin overexpression are high. LST-NG differs from both of these tumor types in that the values of these three indicators are all low.
These results show that LST-G and LST-NG have different genetic alterations.
Journal of Gastroenterology and Hepatology 11/2005; 20(10):1584-90. · 2.87 Impact Factor
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ABSTRACT: It is still not clear which parameters are important for predicting the metastatic potential of superficial esophageal squamous cell carcinoma (SESCC). The purpose of the present paper was thus to investigate tumor cell dissociation (TCD) in SESCC as a predictive factor of lymph node metastasis.
Thirty-three SESCC were classified into four groups based on the depth of tumor invasion. Carcinomas not invading as far as the muscularis mucosa were classified as group A; carcinomas invading to the muscularis mucosa or less than one-third of the upper submucosa were classified as group B; those invading to the middle layer of the submucosa were classified as group C; and those invading one-third of the lower submucosa were classified as group D. The TCD score was calculated by dividing the length of the TCD region by the maximal longitudinal length of the area of invasion into or beyond the lamina propria, and multiplying by 100. E-cadherin expression of the carcinomas was investigated in the TCD area and the successive area of mucosal invasive carcinoma (SAM).
The incidence of lymph node metastasis was 0% in group A, 10% in group B, 36.4% in group C and 57.1% in group D. The mean TCD scores (+/-SEM) of SESCC with lymph node metastasis were higher than that without (85.3 +/- 5.7, 16.3 +/- 3.9, respectively; P < 0.001). In group C, the TCD score of cases with lymph node metastases was higher than in those without lymph node metastasis (P < 0.001). E-cadherin expression was significantly reduced in the area of TCD compared with the SAM located over the TCD area (P < 0.001).
The TCD score is an important predictive marker for lymph node metastasis in SESCC. Clinical evaluation of TCD scores in endoscopic mucosal resection (EMR) specimens would enable accurate prediction of lymph node metastasis and extend the indication of EMR treatment for SESCC.
Journal of Gastroenterology and Hepatology 10/2005; 20(9):1371-8. · 2.87 Impact Factor
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ABSTRACT: Tumor cell dissociation-the histologic finding of small solid carcinoma cell clusters and groups of dissociated dedifferentiated carcinoma cells at the invasive front-is related to tumor metastasis and patient prognosis. However, few previous reports have examined tumor cell dissociation in submucosal invasive colorectal carcinoma. We investigated the relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. We also examined immunohistochemical expression of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma.
Submucosal invasive colorectal carcinoma tissue samples from 20 patients with lymph node metastasis and 100 patients without lymph node metastasis were evaluated. Sections stained with hematoxylin and eosin were evaluated for tumor cell dissociation. Immunohistochemistry was used to determine the expression and cellular distribution of E-cadherin and beta-catenin.
Tumor cell dissociation was more frequently identified in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.0001). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.025). Nuclear expression of beta-catenin tended to be present in submucosal invasive colorectal carcinoma cases with lymph node metastasis (P = 0.063). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with tumor cell dissociation than in those without tumor cell dissociation (P = 0.0023).
Our results suggest that there is a relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. Tumor cell dissociation formation might be related to abnormal expression patterns of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma. Tumor cell dissociation and decreased membranous expression of E-cadherin would be important predictive markers for lymph node metastasis in submucosal invasive colorectal carcinoma.
Diseases of the Colon & Rectum 06/2005; 48(5):938-45. · 3.13 Impact Factor
