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ABSTRACT: Critically shortened telomeres make chromosomes susceptible to the instability and widespread cytogenetic alterations that characterize most human cancers. We hypothesized that the very rapid cell proliferation observed in esophageal squamous cell carcinomas might accelerate telomere shortening and chromosomal instability associated with carcinogenesis. We used a number of telomere measurement techniques including quantitative fluorescence in situ hybridization (Q-FISH) to compare chromosomal aberrations and telomere lengths of individual chromosomes in esophageal squamous cell carcinomas (ESCCs) and nearby non-neoplastic esophageal epithelium (NNEE) cells. Our results showed that the mean telomere length in ESCC cells was significantly less than that in adjacent NNEE cells, and that telomeres in all NNEE cells were significantly shorter than those in normal esophageal epithelium (reported previously). In addition, there was no evidence linking telomere shortening of a particular chromosome to field cancerization in ESCC. However, a mechanistic link between telomere shortening and chromosomal instability was supported by a higher frequency of anaphase/telophase bridges and an increase in the frequency of aneuploidy. This study furthers our understanding of the mechanism by which telomere shortening and chromosomal instability lead to carcinogenesis and field cancerization in the esophagus.
International Journal of Molecular Medicine 01/2008; 20(6):793-9. · 1.98 Impact Factor
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Yoshio Naomoto,
Mehmet Gunduz,
Munenori Takaoka,
Takaomi Okawa,
Esra Gunduz,
Tetsuji Nobuhisa, Masahiko Kobayashi,
Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Ryutaro Sonoda,
Junji Matsuoka,
Noriaki Tanaka
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ABSTRACT: Heparanase has been given attention for its role in the invasion and metastasis of various cancers for years. We have also investigated and reported the role of heparanase in several human cancers, including gastric, esophageal and colon carcinomas. Other than the critical role of heparanase in tumor invasion and metastasis, it is also believed that heparanase is involved in angiogenesis, another feature of tumor progression which is complicatedly mediated by many molecules, including cyclooxygenese-2 (Cox-2). Thus, our recent study elucidated a possible relationship of heparanase with Cox-2 upon tumor angiogenesis. Based upon our study, three major transcription factor binding sites containing NF-kappaB, NF-IL-6 and CRE sites seemed to have a compensative and cooperative role in heparanase-induced Cox-2 upregulation. On the other hand, tumor hypoxia often occurs in most tumors and Cox-2-induced HIF1alpha overexpression has recently been shown in various cancers. Here we believe that heparanase may also be involved in tumor hypoxia through the induction of HIFalpha either directly or indirectly through the Cox-2 pathway. This hypothesis indicates a possible novel function of heparanase and its link to HIF1alpha and Cox-2, and therefore this function would give us a clue about potential new strategies for cancer therapy.
Medical Hypotheses 02/2007; 68(1):162-5. · 1.39 Impact Factor
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Masahiko Kobayashi,
Yoshio Naomoto,
Tetsuji Nobuhisa,
Takaomi Okawa,
Munenori Takaoka,
Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Junji Matsuoka,
Takaaki Mizushima,
Hironori Matsuura,
Motowo Nakajima,
Hiroshi Nakagawa,
Anil Rustgi,
Noriaki Tanaka
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ABSTRACT: Heparanase is an endo-beta-glucuronidase that specifically cleaves heparan sulfate (HS) chains. Heparanase is involved in the process of metastasis and angiogenesis through the degradation of HS chains of the extracellular matrix and cell surface. Recently, we demonstrated that heparanase was localized in the cell nucleus of normal esophageal epithelium and esophageal cancer, and that its expression was correlated with cell differentiation. However, the nuclear function of heparanase remains unknown. To elucidate the role of heparanase in esophageal epithelial differentiation, primary human esophageal cells were grown in monolayer as well as organotypic cultures, and cell differentiation was induced. Expression of heparanase, HS, involucrin, and p27 was determined by immunostaining and Western blotting. SF4, a novel pharmacological inhibitor, was used to specifically inhibit heparanase activity. Upon esophageal cell differentiation, heparanase was translocated from the cytoplasm to the nucleus. Such translocation of heparanase appeared to be associated with the degradation of HS chains in the nucleus and changes in the expression of keratinocyte differentiation markers such as p27 and involucrin, whose induction was inhibited by SF4. Furthermore, these in vitro observations agreed with the expression pattern of heparanase, HS, involucrin, cytokeratin 13, and p27 in normal esophageal epithelium. Nuclear translocation of heparanase and its catalytic cleavage of HS may play a critical role in the differentiation of esophageal epithelial cells. Our study provides a novel insight into the role of heparanase in an essential differentiation process.
Differentiation 07/2006; 74(5):235-43. · 2.81 Impact Factor
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Yasuhiro Shirakawa,
Yoshio Naomoto,
Kazuhiro Noma,
Kazufumi Sakurama,
Toshio Nishikawa,
Tetsuji Nobuhisa, Masahiko Kobayashi,
Takaomi Okawa,
Shinya Asami,
Tomoki Yamatsuji,
Minoru Haisa,
Junji Matsuoka,
Motohiko Hanazaki,
Kiyoshi Morita,
Takao Hiraki,
Noriaki Tanaka
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ABSTRACT: We evaluated the techniques of colonic interposition and supercharge for esophageal reconstruction and discussed the main considerations related to these procedures.
In this study, we performed 51 esophageal reconstructions using colonic interposition. Twenty-eight of the 51 patients had synchronous or allochronic gastric malignancy. We selected colonic interposition for high anastomosis in 11 patients and also for esophageal bypass in 3 patients. This procedure was also selected to preserve gastric function in 5 patients. We recently performed the supercharge technique for colonic interposition in 41 patients.
Despite the long duration and multistep nature of the operation procedure, no perioperative complications were noted. The patients returned to a good quality of life. The incidence of postoperative weight loss did not differ significantly between the colonic reconstruction group and the gastric reconstruction group. In terms of heartburn and dumping syndrome, the outcome was markedly better in the colonic reconstruction group (no cases of heartburn or dumping syndrome) than that in the gastric reconstruction group.
For reconstruction of the esophagus, the colonic interposition and supercharge technique is advantageous and contributes to the patient's quality of life.
Langenbeck s Archives of Surgery 03/2006; 391(1):19-23. · 1.81 Impact Factor
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Sinya Asami,
Yoshio Naomoto,
Tomoki Yamatsuji,
Yasuhiro Shirakawa,
Toshihiro Murata, Masahiko Kobayashi,
Kazufumi Sakurama,
Nobuya Ohara,
Mehmet Gunduz,
Shin Nakatani,
Kaiyo Takubo,
Noriaki Tanaka
Journal of Gastroenterology 02/2006; 41(1):88-9. · 4.16 Impact Factor
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ABSTRACT: There is much interest in precise functions of amino acids on mammalian growth and development. Some of amino acids play important roles in the control of gene expression by controlling the initiation phase of mRNA translation. The signal induced by leucine or arginine may stimulate cell growth. On the other hand, the other signal induced by glutamine may stimulate cellular proliferation and increase cell number, but inhibit the growth of cell size. However, there was no clear evidence that an individual amino acid specifically works as a signaling molecule. In our recent study, not only leucine, but also arginine is shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. Furthermore, regarding L-Glutamine, an important amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells, we have shown that it had an inhibitory effect on leucine- or arginine-induced activation of the mTOR signaling pathway. We have demonstrated that L-Glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Based on these results, we are planning to confirm the effect of each amino acid including glutamine in an in vivo model using new born mice.
International Journal of Molecular Medicine 09/2005; 16(2):201-4. · 1.98 Impact Factor
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Norifumi Mino,
Yoshio Naomoto,
Yasuhiro Shirakawa,
Junji Matsuoka,
Tetsuji Nobuhisa,
Mehmet Gunduz,
Kazuhiro Noma,
Hitoshi Nagatsuka, Masahiko Kobayashi,
Tomoki Yamatsuji,
Minoru Haisa,
Akira Gochi,
Noriaki Tanaka
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ABSTRACT: Perforin is known as a pore-forming cytotoxic granule released from cytotoxic T cells. Previous experiments in vitro revealed the presence of precursor cells that are capable of producing perforin in the immune system cells. The present study was undertaken to examine whether perforin-positive cells could be induced in the digestive tract and to characterize their precursor cells. Expression of perforin-positive cells in the intestine of Balb/c mice induced by OK-432 was analyzed by immunohistochemical staining and RT-PCR. Oral treatment of Balb/c mice with OK-432 resulted in the occurrence of perforin-positive cells in the inferior segment of small intestine, the superior segment of large intestine, mesenteric lymph nodes and spleen. In the small intestine, perforin-positive cells were found in the lamina propria mucosa. The presence of perforin-positive cells was also noted following long-term OK-432 treatment. Similar results were obtained following treatment with biological response modifiers such as lipopolysaccharide. In mice with GVHD (graft-versus-host disease), the presence of perforin-positive cells was noted in the small intestine and spleen. When the serial sections of the small intestinal mucosa from OK-432-treated mice were immunostained with anti-perforin, anti-CD8 and anti-asialo-GM1 antibodies, the perforin-positive cells were found to be CD8-positive. The results suggest that CD8(+) cells in lamina propria mucosa play a significant role as effectors in the mucosal immune system which is activated by various stimuli.
International Journal of Molecular Medicine 12/2004; 14(5):801-6. · 1.98 Impact Factor
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Takaomi Ohkawa,
Yoshio Naomoto,
Munenori Takaoka,
Tetsuji Nobuhisa,
Kazuhiro Noma,
Takayuki Motoki,
Toshihiro Murata,
Hirokazu Uetsuka, Masahiko Kobayashi,
Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Nagahide Matsubara,
Junji Matsuoka,
Minoru Haisa,
Mehmet Gunduz,
Hidetsugu Tsujigiwa,
Hitoshi Nagatsuka,
Masao Hosokawa,
Motowo Nakajima,
Noriaki Tanaka
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ABSTRACT: In this study, we examined the distribution of heparanase protein in 75 esophageal squamous cell carcinomas by immunohistochemistry and analyzed the relationship between heparanase expression and clinicopathological characteristics. In situ hybridization showed that the mRNA expression pattern of heparanase was similar to that of the protein, suggesting that increased expression of the heparanase protein at the invasive front was caused by an increase of heparanase mRNA in tumor cells. Heparanase expression correlated significantly with depth of tumor invasion, lymph node metastasis, tumor node metastasis (TNM) stage and lymphatic invasion. Overexpression of heparanase in esophageal cancers was also associated with poor survival. In addition to its localization in the cytoplasm and cell membrane, heparanase was also identified in the nuclei of normal epithelial and tumor cells by immunohistochemistry. Furthermore, nuclear heparanase was detected in nuclear extract of cancer cell lines by Western blot and immunohistochemistry. Examination of the role of nuclear heparanase in cell proliferation and differentiation by double immunostaining for proliferating cell nuclear antigen (PCNA) and cytokeratin 10 (CK10) showed significant relationship between nuclear heparanase expression and differentiation (heparanase vs CK10), but not for proliferative state of esophageal cancer cells (heparanase vs PCNA). Our results suggest that cytoplasmic heparanase appears to be a useful prognostic marker in patients with esophageal cancer and that nuclear heparanase protein may play a role in differentiation. Inhibition of heparanase activity may be effective in the control of esophageal tumor invasion and metastasis.
Laboratory Investigation 11/2004; 84(10):1289-304. · 3.64 Impact Factor
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Yasuhiro Shirakawa,
Yoshio Naomoto,
Kazuhiro Noma,
Ryoko Ono,
Tetsuji Nobuhisa, Masahiko Kobayashi,
Toshiya Fujiwara,
Hirofumi Noguchi,
Takaomi Ohkawa,
Tomoki Yamatsuji,
Minoru Haisa,
Junji Matsuoka,
Mehmet Gunduz,
Noriaki Tanaka
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ABSTRACT: This study assessed the techniques of the free jejunal graft for the reconstruction of hypopharynx or cervical esophagus and discussed the main aspects related to those procedures.
By using free jejunal grafts, we reconstructed 54 hypopharyngeal and cervical esophageal cancers. In this study, 23 out of 54 patients had a malignant tumor located in the hypopharynx and 31 in the cervical esophagus (27 primary cases and four secondary cases). Despite the multi-step and time-consuming procedure, we did not incur any trans-operative complication. Furthermore, we undertook the larynx preserving cervical esophagectomy and free jejunal graft reconstruction in six patients with cervical esophageal cancer, and those patients acquired a good quality of life.
For the reconstruction of hypopharynx or cervical esophagus, the free jejunal graft is a very useful technique and improves the patient's quality of life.
Langenbeck s Archives of Surgery 11/2004; 389(5):387-90. · 1.81 Impact Factor
