研究者詳細 - 鈴木　拓

論文 - 鈴木　拓

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新沼猛, 鈴木拓, 篠村恭久

成人病と生活習慣病 ( (株)東京医学社 ) 41 ( 6 ) 735 - 737 2011年06月

・消化管間葉系腫瘍の多くを占めるGISTのマーカーとしてはKITの発現が広く用いられている。・一部のKIT陰性のGISTに対してPKCθ、DOG1などの発現を検索することが有用であることがある。・GISTにおいては悪性度や予後と相関するとされるさまざまなマーカーが用いられており、細胞増殖の指標として用いられているMIB-1 labeling indexのほかにも、癌抑制遺伝子であるp16の発現低下やT細胞活性化抗原であるCD26の高発現が高リスク、予後不良と関連すると報告されている。・その他の間葉系腫瘍としては平滑筋腫瘍、神経性腫瘍、血管性腫瘍、線維芽細胞性腫瘍があり、平滑筋腫瘍においてはactinやmyosinが、神経性腫瘍においてはS100やGFAP(glial fibrillary acidic protein)、血管性腫瘍においては内皮系のマーカーであるCD31、CD34、von Willebrand因子などが用いられている。・線維芽細胞性腫瘍のうち腸間膜線維腫症においてはβ-cateninの発現上昇が認められることが多く診断の一助となる。(著者抄録)

Interferon-α/β and anti-fibroblast growth factor receptor 1 monoclonal antibody suppress hepatic cancer cells in vitro and in vivo.

Sasaki S, Ishida T, Toyota M, Ota A, Suzuki H, Takaoka A, Yasui H, Yamamoto H, Takagi H, Maeda M, Seito T, Tsujisaki M, Shinomura Y, Imai K

PloS one ( PUBLIC LIBRARY SCIENCE ) 6 ( 5 ) e19618 2011年05月 [査読有り]

Background: Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC. Methodology/Principal Findings: We used Western blot and flow cytometric and immunocytochemical analyses to investigate the regulation of FGFR1 expression by interferon-alpha/beta in several human hepatic cancer cell lines. In addition, we tested the efficacy of combined treatment with anti-FGFR1 monoclonal antibody and interferon-alpha/beta in a murine xenograft model of human HCC. We found that interferon-alpha/beta induces expression of FGFR1 in human HCC cell lines, and that an anti-FGFR1 monoclonal antibody (mAb) targeting of the induced FGFR1 can effectively inhibit growth and survival of HCC cells in vitro and in vivo. Moreover, the combination of interferon-alpha, anti-FGFR1 mAb and peripheral blood mononuclear cells (PBMCs) exerted a significant antitumor effect in vitro. Conclusions: Our results suggest that the combined use of an anti-FGFR1 antibody and interferon-alpha/beta is a promising approach to the treatment of HCC.

DOI PubMed

Epigenetic Alteration of DNA in Mucosal Wash Fluid Predicts Invasiveness of Colorectal Tumors

Seiko Kamimae, Eiichiro Yamamoto, Hiro-o Yamano, Masanori Nojima, Hiromu Suzuki, Masami Ashida, Tomo Hatahira, Akiko Sato, Tomoaki Kimura, Kenjiro Yoshikawa, Taku Harada, Seiko Hayashi, Hiroyuki Takamaru, Reo Maruyama, Masahiro Kai, Morie Nishiwaki, Tamotsu Sugai, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Minoru Toyota

CANCER PREVENTION RESEARCH ( AMER ASSOC CANCER RESEARCH ) 4 ( 5 ) 674 - 683 2011年05月 [査読有り]

Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors, We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest. that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors. Cancer Prey Res; 4(5); 674-83. (c) 2011 AACR.

DOI PubMed

Molecular analysis of gastrointestinal tumor and translational research

Hiroyuki Yamamoto, Hiromu Suzuki, Yasushi Adachi, Yasuhisa Shinomura

Journal of Japanese Society of Gastroenterology 108 ( 1 ) 1 - 10 2011年01月 [査読有り]

PubMed

消化器癌の分子解析とトランスレーショナルリサーチ

山本博幸, 鈴木拓, 足立靖, 篠村恭久

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 108 ( 1 ) 1 - 10 2011年01月

消化器癌の分野においても、医療につながる基礎研究成果を臨床に実用化させるトランスレーショナルリサーチ(橋渡し研究)が盛んである。大規模な医薬品開発などをともなわなくとも、消化器癌の分子解析の結果を臨床にトランスレートすることが可能となってきた。本稿では、ゲノムワイドな低メチル化、CpG island methylator phenotype(CIMP)、microRNA(miRNA)、microsatellite instability(MSI)、insulin-like growth factor-I receptor(IGF-IR)に関して最近のデータを中心に紹介し、近未来的な展望についても概説する。(著者抄録)

Gastric Wash-Based Molecular Testing for Antibiotic Resistance in Helicobacter pylori

Satoshi Baba, Yoshichika Oishi, Yoshiyuki Watanabe, Ritsuko Oikawa, Ryo Morita, Yoshihito Yoshida, Tetsuya Hiraishi, Tadateru Maehata, Yoshihiko Nagase, Yasunobu Fukuda, Midori Nakazawa, Shinya Ishigouoka, Nobuhiro Hattori, Hiromu Suzuki, Minoru Toyota, Hirohumi Niwa, Michihiro Suzuki, Fumio Itoh

DIGESTION ( KARGER ) 84 ( 4 ) 299 - 305 2011年 [査読有り]

Background: A number of noninvasive tests have been developed to establish the presence of Helicobacter pylori infection. However, thus far these tests have only been capable of detecting its presence. An increasing number of antibiotic-resistant H. pylori infections have been reported and they are known to be correlated with 23S rRNA single nucleotide polymorphisms (SNPs). We hypothesized that genomic analysis of H. pylori recovered from gastric washes could not only be less invasive, but also useful as a screening test and for assessing the outcome of eradication therapy. Methods: Biopsy specimens and gastric washes were collected from 100 patients during endoscopic examination. Then we analyzed 23S rRNA, ureA, and cagA genes using PCR and high-throughput pyrosequencing analysis. Results: Forty-five percent (44/97) of patients tested positive for ureA and 42.3% (41/97) tested positive by a rapid urease test. One hundred percent (35/35) of patients who tested positive by both methods were observed to have the cagA gene. Among these 35 patients, 23S rRNA SNPs were present in 34.3% (12/35). Conclusions: Gastric wash-based PCR and a pyrosequencing assay were used to rapidly detect and estimate the number of 23S rRNA SNPs in clinical isolates of H. pylori. Not only is this a less invasive technique, but it can also diagnose drug resistance. Copyright (C) 2011 S. Karger AG, Basel

DOI PubMed

Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer

Eiichiro Yamamoto, Hiromu Suzuki, Hiroyuki Takamaru, Hiroyuki Yamamoto, Minoru Toyota, Yasuhisa Shinomura

DIGESTION ( KARGER ) 83 ( 4 ) 241 - 249 2011年 [査読有り]

Cancer cells exhibit two opposing methylation abnormalities: genome-wide hypomethylation and gene promoter hypermethylation. Downregulation of E-cadherin (CDH1) plays a key role in the development of diffuse-type gastric cancer, and DNA methylation is a major cause of the gene's silencing. Hereditary diffuse gastric cancer is caused by germline mutation of CDH1 gene, and DNA methylation frequently serves as the second hit completely inactivating the gene. In sporadic diffuse-type gastric cancer, methylation of CDH1 is more prevalent than mutation of the gene. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBV-associated GC) is characterized by concurrent methylation of multiple genes, and diffuse-type gastric cancer is frequently seen among EBV-associated GCs. Patients with pangastritis or enlarged-fold gastritis, which are both caused by Helicobacter pylori infection, reportedly have an increased risk for diffuse-type gastric cancer. Notably, the gastric mucosa of enlarged-fold gastritis patients exhibits CDH1 hypermethylation and genome-wide hypomethylation. These data suggest that aberrant DNA methylation is an essential promoter of carcinogenesis in individuals at high risk for diffuse-type gastric cancer. Copyright (C) 2011 S. Karger AG, Basel

DOI PubMed

Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect

Hiromu Suzuki, Eiichiro Yamamoto, Masanori Nojima, Masahiro Kai, Hiro-o Yamano, Kenjiro Yoshikawa, Tomoaki Kimura, Toyoki Kudo, Eiji Harada, Tamotsu Sugai, Hiroyuki Takamaru, Takeshi Niinuma, Reo Maruyama, Hiroyuki Yamamoto, Takashi Tokino, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

CARCINOGENESIS ( OXFORD UNIV PRESS ) 31 ( 12 ) 2066 - 2073 2010年12月 [査読有り]

Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2'-deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk.

DOI PubMed

学内研究紹介がんのエピジェネティクス異常の解明と臨床応用

鈴木拓, 山本博幸, 篠村恭久

札幌医学雑誌 ( 札幌医科大学医学部 ) 79 ( 1 ) 1 - 5 2010年12月

Cancer is fundamentally a genetic and epigenetic disease that requires the accumulation of genomic alterations that inactivate tumor suppressors and activate proto-oncogenes. Two contradicting epigenetic events coexist in cancer: global hypomethylation, which is mainly observed in repetitive sequences within the genome, and regional hypermethylation, which is frequently associated with CpG islands within gene promoters. Hypermethylation alters the activity in a number of important signaling pathways by silencing expression of genes encoding Wnt antagonists, negative Ras effectors, and p53 targets. The list of genes aberrantly methylated in cancer is growing, and methylation of a p53 target micoRNA gene has been recently demonstrated. Global hypomethylation is strongly implicated in chromosomal instability and malignant potential of tumors. Sites of aberrant DNA methylation could be promising markers and targets for risk assessment, early detection and treatment of cancer.

DOI CiNii

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Shinichi Igarashi, Hiromu Suzuki, Takeshi Niinuma, Haruo Shimizu, Masanori Nojima, Hiroyuki Iwaki, Takayuki Nobuoka, Toshirou Nishida, Yasuaki Miyazaki, Hiroyuki Takamaru, Eiichiro Yamamoto, Hiroyuki Yamamoto, Takashi Tokino, Tadashi Hasegawa, Koichi Hirata, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

CLINICAL CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 16 ( 21 ) 5114 - 5123 2010年11月 [査読有り]

Purpose: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. Experimental Design: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-a, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using Methy-Light. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens. Results: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-a and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. Conclusions: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. Clin Cancer Res; 16(21); 5114-23. (C)2010 AACR.

DOI PubMed

Genomic screening for genes upregulated by demethylation revealed novel targets of epigenetic silencing in breast cancer

Tomoko Fujikane, Noriko Nishikawa, Minoru Toyota, Hiromu Suzuki, Masanori Nojima, Reo Maruyama, Masami Ashida, Mutsumi Ohe-Toyota, Masahiro Kai, Toshihiko Nishidate, Yasushi Sasaki, Tousei Ohmura, Koichi Hirata, Takashi Tokino

BREAST CANCER RESEARCH AND TREATMENT ( SPRINGER ) 122 ( 3 ) 699 - 710 2010年08月 [査読有り]

Breast cancer arises through the accumulation of multiple genetic alterations and epigenetic changes such as methylation, which silences gene expression in a variety of cancers. In the present study, we applied genomic screening to identify genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine (DAC) in a human breast cancer cell line (MCF7). We identified 288 genes upregulated and 29 genes downregulated more than fivefold after treatment with DAC, and gene ontology analyses revealed the genes to be involved in immune responses, apoptosis, and cell differentiation. In addition, real-time PCR analysis of ten genes silenced in MCF7 cells confirmed that they are upregulated by DAC, while bisulfite-pyrosequencing analysis confirmed that nine of those genes were silenced by methylation. We also found that treating MCF7 cells with DAC restored induction of DFNA5 by p53, as well as by two other p53 family genes, p63 gamma and p73 beta. Introduction of NTN4 into MCF7 cells suppressed cell growth, indicating that NTN4 has tumor suppressive activity. In primary breast cancers, we detected cancer-specific methylation of NTN4, PGP9.5, and DKK3, suggesting that methylation of these genes could be useful markers for diagnosis of breast cancer. Thus, DNA methylation appears to be a common event in breast cancer, and the genes silenced by methylation could be useful targets for both diagnosis and therapy.

DOI PubMed

p53により発現抑制される分泌性増殖因子HDGFの同定(Negative regulation of hepatoma-derived growth factor by p53)

佐々木泰史, 根岸秀明, 横田育子, 鹿島理沙, 井戸川雅史, 鈴木拓, 豊田実, 今井浩三, 篠村恭久, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 69回 303 - 303 2010年08月

次世代シークエンサーを用いた遺伝子転写開始点予測とエピゲノム解析への応用(Prediction of transcription start sites using next-generation sequencer and its application to epigenome analysis)

豊田実, 鈴木拓, 野島正寛, 佐々木泰史, 篠村恭久, 時野隆至, 今井浩三

日本癌学会総会記事 ( (一社)日本癌学会 ) 69回 417 - 417 2010年08月

肝細胞癌におけるLINE-1低メチル化とCpGアイランド高メチル化の意義(Implications of LINE-1 hypomethylation and CpG island hypermethylation in hepatocellular carcinoma)

谷口博昭, 山本博幸, 阿久津典之, 佐々木茂, 足立靖, 大橋広和, 田沼徳真, 宮本千絵, 宮本伸樹, 鈴木拓, 有村佳昭, 今井浩三, 篠村恭久

日本癌学会総会記事 ( (一社)日本癌学会 ) 69回 246 - 246 2010年08月

DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae

Masaki Yamashita, Minoru Toyota, Hiromu Suzuki, Masanori Nojima, Eiichiro Yamamoto, Seiko Kamimae, Yoshiyuki Watanabe, Masahiro Kai, Hirofumi Akashi, Reo Maruyama, Yasushi Sasaki, Hiroo Yamano, Tamotsu Sugai, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino, Fumio Itoh

CANCER SCIENCE ( WILEY-BLACKWELL ) 101 ( 7 ) 1708 - 1716 2010年07月 [査読有り]

Interferon regulatory factors (IRFs) are transcription factors known to play key roles in innate and adaptive immune responses, cell growth, apoptosis, and development. Their function in tumorigenesis of gastric cancer remains to be determined, however. In the present study, therefore, we examined epigenetic inactivation of IRF1-9 in a panel of gastric cancer cell lines. We found that expression of IRF4, IRF5, and IRF8 was frequently suppressed in gastric cancer cell lines; that methylation of the three genes correlated with their silencing; and that treating the cells with the demethylating agent 5-aza-2'-deoxycytidine (DAC) restored their expression. Expression of IRF5 in cancer cells was enhanced by the combination of DAC treatment and adenoviral vector-mediated expression of p53, p63, or p73. Interferon-gamma-induced expression of IRF8 was also enhanced by DAC. Moreover, treating gastric cancer cells with DAC enhanced the suppressive effects of interferon-alpha, interferon-beta, and interferon-gamma on cell growth. Among a cohort of 455 gastric cancer and noncancerous gastric tissue samples, methylation of IRF4 was frequently observed in both gastric cancer specimens and noncancerous specimens of gastric mucosa from patients with multiple gastric cancers, which suggests IRF4 methylation could be a useful molecular marker for diagnosing recurrence of gastric cancers. Our findings indicate that epigenetic IRF inactivation plays a key role in tumorigenesis of gastric cancer, and that inhibition of DNA methylation may restore the antitumor activity of interferons through up-regulation of IRFs. (Cancer Sci 2010).

DOI PubMed

多発性骨髄腫におけるDNAメチル化の網羅的解析と治療抵抗性予測への応用

安井寛, 石田禎夫, 野島正寛, 青木由佳, 丸山玲緒, 多羅澤功, 池田博, 鈴木拓, 林敏昭, 酒井基, 麻奥英毅, 今井浩三, 篠村恭久, 豊田実

生物物理化学 ( 日本電気泳動学会 ) 54 ( Suppl. ) 18 - 18 2010年07月

Array-based genomic resequencing of human leukemia

Y. Yamashita, J. Yuan, I. Suetake, H. Suzuki, Y. Ishikawa, Y. L. Choi, T. Ueno, M. Soda, T. Hamada, H. Haruta, S. Takada, Y. Miyazaki, H. Kiyoi, E. Ito, T. Naoe, M. Tomonaga, M. Toyota, S. Tajima, A. Iwama, H. Mano

Oncogene 29 ( 25 ) 3723 - 3731 2010年06月 [査読有り]

To identify oncogenes in leukemias, we performed large-scale resequencing of the leukemia genome using DNA sequence arrays that determine ∼9 Mbp of sequence corresponding to the exons or exon-intron boundaries of 5648 protein-coding genes. Hybridization of genomic DNA from CD34-positive blasts of acute myeloid leukemia (n=19) or myeloproliferative disorder (n=1) with the arrays identified 9148 nonsynonymous nucleotide changes. Subsequent analysis showed that most of these changes were also present in the genomic DNA of the paired controls, with 11 somatic changes identified only in the leukemic blasts. One of these latter changes results in a Met-to-Ile substitution at amino-acid position 511 of Janus kinase 3 (JAK3), and the JAK3(M511I) protein exhibited transforming potential both in vitro and in vivo. Further screening for JAK3 mutations showed novel and known transforming changes in a total of 9 out of 286 cases of leukemia. Our experiments also showed a somatic change responsible for an Arg-to-His substitution at amino-acid position 882 of DNA methyltransferase 3A, which resulted in a loss of DNA methylation activity of > 50%. Our data have thus shown a unique profile of gene mutations in human leukemia. © 2010 Macmillan Publishers Limited All rights reserved.

DOI PubMed

IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype

Hiromu Suzuki, Shinichi Igarashi, Masanori Nojima, Reo Maruyama, Eiichiro Yamamoto, Masahiro Kai, Hirofumi Akashi, Yoshiyuki Watanabe, Hiroyuki Yamamoto, Yasushi Sasaki, Fumio Itoh, Kohzoh Imai, Tamotsu Sugai, Lanlan Shen, Jean-Pierre J. Issa, Yasuhisa Shinomura, Takashi Tokino, Minoru Toyota

CARCINOGENESIS ( OXFORD UNIV PRESS ) 31 ( 3 ) 342 - 349 2010年03月 [査読有り]

A subset of colorectal cancers (CRCs) show simultaneous methylation of multiple genes; these tumors have the CpG island methylator phenotype (CIMP). CRCs with CIMP show a specific pattern of genetic alterations, including a high frequency of BRAF mutations and a low frequency of p53 mutations. We therefore hypothesized that genes inactivated by DNA methylation are involved in the BRAF- and p53-signaling pathways. Among those, we examined the epigenetic inactivation of insulin-like growth factor-binding protein 7 (IGFBP7) expression in CRCs. We found that in CRC cell lines, the silencing of IGFBP7 expression was correlated with high levels of DNA methylation and low levels of histone H3K4 methylation. Luciferase and chromatin immunoprecipitation assays in unmethylated cells revealed that p53 induces expression of IGFBP7 upon binding to a p53 response element within intron 1 of the gene. Treating methylated CRC cell lines with 5-aza-2'-deoxycytidine restored p53-induced IGFBP7 expression. Levels of IGFBP7 methylation were also significantly higher in primary CRC specimens than in normal colonic tissue (P < 0.001). Methylation of IGFBP7 was correlated with BRAF mutations, an absence of p53 mutations and the presence of CIMP. Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence.

DOI PubMed

Polymorphisms in estrogen related genes may modify the protective effect of isoflavones against prostate cancer risk in Japanese men

Tomoko Sonoda, Hiromu Suzuki, Mitsuru Mori, Taiji Tsukamoto, Akira Yokomizo, Seiji Naito, Kiyohide Fujimoto, Yoshihiko Hirao, Naoto Miyanaga, Hideyuki Akaza

EUROPEAN JOURNAL OF CANCER PREVENTION ( LIPPINCOTT WILLIAMS & WILKINS ) 19 ( 2 ) 131 - 137 2010年03月 [査読有り]

Soy isoflavones and estrogen related genes may play a major role in the etiology of prostate cancer. This study examined whether the genetic polymorphisms of estrogen receptors (ESR-alpha and ESR-beta) and cytochrome P450 19A1 (CYP19A1) modified the protective effect of isoflavones against prostate cancer. One hundred and eighty cases and 177 controls were selected from three geographic areas of Japan. The odds ratio for more than or equal to 60 versus less than 60 mg/day of the intake of isoflavones was 0.63 (95% confidence interval = 0.41-0.96). The TTTA long repeat was significantly associated with an increased risk (odds ratio = 1.76, 95% confidence interval = 1.15-5.70). The interaction between the polymorphisms and the intake of isoflavones on prostate cancer risk was analyzed by the multifactor dimensionality reduction method. The combination of the TTTA long repeats and the minor alleles of rs10046 in CYP19A1 and rs2077647 in ESR-alpha was a high risk for prostate cancer despite greater than or equal to 60 mg isoflavones/day. The combination of the TTTA short repeat and those homozygous for the major allele of rs10046 in CYP19A1 was low risk despite less than 60 mg isoflavones/day. In conclusion, the findings of this case-control study suggest that the protective effect of isoflavones may differ between the genotypes of estrogen related genes. European Journal of Cancer Prevention 19: 131-137 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

DOI PubMed

Immune response against tumor antigens expressed on human cancer stem-like cells/tumor-initiating cells

Yoshihiko Hirohashi, Toshihiko Torigoe, Satoko Inoda, Akari Takahashi, Rena Morita, Satoshi Nishizawa, Yasuaki Tamura, Hiromu Suzuki, Minoru Toyota, Noriyuki Sato

IMMUNOTHERAPY ( FUTURE MEDICINE LTD ) 2 ( 2 ) 201 - 211 2010年03月 [査読有り]

Cancer stem-like cells (CSCs)/tumor-initiating cells (TICs) are a small population of cancer cells that have the properties of tumor-initiating ability, self-renewal and differentiation. These properties suggest that CSCs/TICs are essential for tumor maintenance, recurrence and distant metastasis. Thus, elimination of CSCs/TICs is essential to cure malignant diseases. However, there are several studies reporting that CSCs/TICs are more resistant to standard cancer therapies, including chemotherapy and radiotherapy, than nonCSC/TIC populations. How then, can we eliminate CSCs/TICs? Immunotherapy might be the possible answer. In recent analysis, innate immunity (natural killer cells and gamma delta T cells) and also adaptive immunity (cytotoxic T lymphocyte-based cellular immunity and antibody-based humoral immunity) can recognize CSCs/TICs in vitro efficiently. Furthermore, CSC/TIC-specific monoclonal antibody therapies are also efficient in vivo. In this article, we describe the potency, possibilities and problems of CSC/TIC-targeting immunotherapy.

DOI PubMed

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