Details of a Researcher - SUZUKI Hiromu

Papers - SUZUKI Hiromu

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Upregulation of adenylate cyclase 3 (ADCY3) increases the tumorigenic potential of cells by activating the CREB pathway

Seung-Hyun Hong, Sung-Ho Goh, Sang Jin Lee, Jung-Ah Hwang, Jieun Lee, Il-Ju Choi, Hyehyun Seo, Jong-Hoon Park, Hiromu Suzuki, Eiichiro Yamamoto, In-Hoo Kim, Jin Sook Jeong, Mi Ha Ju, Dong-Hee Lee, Yeon-Su Lee

Oncotarget ( Impact Journals LLC ) 4 ( 10 ) 1791 - 1803 2013 [Refereed]

Adenylate cyclase 3 (ADCY3) is a widely expressed membrane-associated protein in human tissues, which catalyzes the formation of cyclic adenosine-3′,5′-monophosphate (cAMP). However, our transcriptome analysis of gastric cancer tissue samples (NCBI GEO GSE30727) revealed that ADCY3 expression was specifically altered in cancer samples. Here we investigated the tumor-promoting effects of ADCY3 overexpression and confirmed a significant correlation between the upregulation of ADCY3 and Lauren's intestinal-type gastric cancers. ADCY3 overexpression increased cell migration, invasion, proliferation, and clonogenicity in HEK293 cells conversely, silencing ADCY3 expression in SNU-216 cells reduced these phenotypes. Interestingly, ADCY3 overexpression increased both the mRNA level and activity of matrix metalloproteinase 2 (MMP2) and MMP9 by increasing the levels of cAMP and phosphorylated cAMP-responsive element-binding protein (CREB). Consistent with these findings, treatment with a protein kinase A (PKA) inhibitor decreased MMP2 and MMP9 expression levels in ADCY3-overexpressing cells. Knockdown of ADCY3 expression by stable shRNA in human gastric cancer cells suppressed tumor growth in a tumor xenograft model. Thus, ADCY3 overexpression may exert its tumor-promoting effects via the cAMP/PKA/CREB pathway. Additionally, bisulfite sequencing of the ADCY3 promoter region revealed that gene expression was reduced by hypermethylation of CpG sites, and increased by 5-Aza-2′-deoxycytidine (5-AzadC)-induced demethylation. Our study is the first to report an association of ADCY3 with gastric cancer as well as its tumorigenic potentials. In addition, we demonstrate that the expression of ADCY3 is regulated through an epigenetic mechanism. Further study on the mechanism of ADCY3 in tumorigenesis will provide the basis as a new molecular target of gastric cancer.

DOI PubMed

Analysis of LINE-1 methylation level and microRNA expression in CRC for identifying a new biomarker

Igarashi Hisayoshi, Nosho Katsuhiko, Ito Miki, Naito Takafumi, Kunimoto Hiroaki, Sukawa Yasutaka, Yoshii Shinji, Yamamoto Eiichiro, Suzuki Hiromu, Yamamoto Hiroyuki, Adachi Yasushi, Shinomura Yasuhisa

Japan Journal of Molecular Tumor Marker Research ( Japanese Society for Molecular Tumor Marker Research ) 28 62 - 63 2013

DOI CiNii

New detection method for integrating Hepatitis B Virus DNA Sequences in PLC/PRF/5 Cell Line

Hiraishi Tetsuya, Watanabe Yoshiyuki, Oikawa Ritsuko, Yamada Norie, Okuse Chiaki, Suzuki Hiromu, Yotsuyanagi Hiroshi, Suzuki Michihiro, Itoh Fumio

Japan Journal of Molecular Tumor Marker Research ( Japanese Society for Molecular Tumor Marker Research ) 28 53 - 53 2013

DOI CiNii

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

Yasutaka Sukawa, Hiroyuki Yamamoto, Katsuhiko Nosho, Hiroaki Kunimoto, Hiromu Suzuki, Yasushi Adachi, Mayumi Nakazawa, Takayuki Nobuoka, Mariko Kawayama, Masashi Mikami, Takashi Matsuno, Tadashi Hasegawa, Koichi Hirata, Kohzoh Imai, Yasuhisa Shinomura

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBL GRP CO LTD ) 18 ( 45 ) 6577 - 6586 2012.12 [Refereed]

AIM: To investigate human epidermal growth factor receptor 2 (HER2)-phosphatidylinositol 3-kinase (PI3K)-v-Akt murine thymoma viral oncogene homolog signaling pathway. METHODS: We analyzed 231 formalin-fixed, paraffin-embedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment. The patients' age, sex, tumor location, depth of invasion, pathological type, lymph node metastasis, and pathological stage were determined by a review of the medical records. Expression of HER2 was analyzed by immunohistochemistry (IHC) using the HercepTes (TM) kit. Standard criteria for HER2 positivity (0, 1+, 2+, and 3+) were used. Tumors that scored 3+ were considered HER2-positive. Expression of phospho Akt (pAkt) was also analyzed by IHC. Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more. PI3K, catalytic, alpha polypeptide (PIK3CA) mutations in exons 1, 9 and 20 were analyzed by pyrosequencing. Epstein-Barr virus (EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA (EBER) with an EBER-RNA probe. Microsatellite instability (MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26. RESULTS: HER2 expression levels of 0, 1+, 2+ and 3+ were found in 167 (72%), 32 (14%), 12 (5%) and 20 (8.7%) samples, respectively. HER2 overexpression (IHC 3+) significantly correlated with intestinal histological type (15/20 vs 98 /205, P = 0.05). PIK3CA mutations were present in 20 cases (8.7%) and significantly correlated with MSI (10/20 vs 9/211, P < 0.01). The mutation frequency was high (21%) in T4 cancers and very low (6%) in T2 cancers. Mutations in exons 1, 9 and 20 were detected in 5 (2%), 9 (4%) and 7 (3%) cases, respectively. Two new types of PIK3CA mutation, R88Q and R108H, were found in exon1. All PIK3CA mutations were heterozygous missense single-base substitutions, the most common being H1047R (6/20, 30%) in exon20. Eighteen cancers (8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type (13/18 vs 93/198, P = 0.04). There were 7 cases of lymphoepithelioma-like carcinomas (LELC) and 6 of those cases were EBV-positive (percent/EBV: 6/18, 33%; percent/all LELC: 6/7, 86%). pAkt expression was positive in 119 (53%) cases but showed no correlation with clinicopathological characteristics. pAkt expression was significantly correlated with HER2 overexpression (16/20 vs 103/211, P < 0.01) but not with PIK3CA mutations (12/20 vs 107/211, P = 0.37) or EBV infection (8/18 vs 103/211, P = 0.69). The frequency of pAkt expression was higher in cancers with exon20 mutations (100%) than in those with exon1 (40%) or exon9 (56%) mutations. One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection. However, no cases showed both PIK3CA mutations and HER2 overexpression. One EBV-positive cancer with PIK3CA mutation (H1047R) was MSI-positive. Three of these 4 cases were positive for pAkt expression. In survival analysis, pAkt expression significantly correlated with a poor prognosis (hazard ratio 1.75; 95%CI: 1.12-2.80, P = 0.02). CONCLUSION: HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized. pAkt expression significantly correlates with HER2 expression and with a poor prognosis.

DOI PubMed

Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma

Yuka Aoki, Masanori Nojima, Hiromu Suzuki, Hiroshi Yasui, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, Mitsuhiro Itagaki, Hideki Asaoku, Hiroshi Ikeda, Toshiaki Hayashi, Kohzoh Imai, Mitsuru Mori, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura

GENOME MEDICINE ( BIOMED CENTRAL LTD ) 4 ( 12 ) 101 2012.12 [Refereed]

Background: The aim of this study was to clarify the role of global hypomethylation of repetitive elements in determining the genetic and clinical features of multiple myeloma (MM). Methods: We assessed global methylation levels using four repetitive elements (long interspersed nuclear element-1 (LINE-1), Alu Ya5, Alu Yb8, and Satellite-a) in clinical samples comprising 74 MM samples and 11 benign control samples (7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPC)). We also evaluated copy-number alterations using array-based comparative genomic hybridization, and performed methyl-CpG binding domain sequencing (MBD-seq). Results: Global levels of the repetitive-element methylation declined with the degree of malignancy of plasma cells (NPC>MGUS>MM), and there was a significant inverse correlation between the degree of genomic loss and the LINE-1 methylation levels. We identified 80 genomic loci as common breakpoints (CBPs) around commonly lost regions, which were significantly associated with increased LINE-1 densities. MBD-seq analysis revealed that average DNA-methylation levels at the CBP loci and relative methylation levels in regions with higher LINE-1 densities also declined during the development of MM. We confirmed that levels of methylation of the 5' untranslated region of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and poorer overall survival (hazard ratio 2.8, P = 0.015). Conclusion: Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.

DOI PubMed

CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion

Yasushi Sasaki, Ryota Koyama, Reo Maruyama, Takehiro Hirano, Miyuki Tamura, Jun Sugisaka, Hiromu Suzuki, Masashi Idogawa, Yasuhisa Shinomura, Takashi Tokino

CANCER BIOLOGY & THERAPY ( LANDES BIOSCIENCE ) 13 ( 14 ) 1512 - 1521 2012.12 [Refereed]

The tumor suppressor p53 transcriptionally regulates a number of genes that are involved in cell-cycle inhibition, apoptosis and the maintenance of genetic stability. Recent studies suggest that p53 also contributes to the regulation of cell migration and invasion. Here, we show that human chloride channel accessory-2 (CLCA2) is a target gene of the p53 family (p53, p73 and p63). CLCA2 is induced by DNA damage in a p53-dependent manner. The p53 family proteins activate the CLCA2 promoter by binding directly to the conserved consensus p53-binding site present in the CLCA2 promoter. In terms of function, ectopic expression of CLCA2 inhibited cancer cell migration. In contrast, silencing CLCA2 with siRNA stimulated cancer cell migration and invasion. We also found that inactivation of CLCA2 enhanced the expression of focal adhesion kinase (FAK), as well as its promoter activation. A small-molecule FAK inhibitor reduced the effect of CLCA2 siRNA on cell migration and invasion, suggesting that CLCA2 inhibits cancer cell migration and invasion through suppression of the FAK signaling pathway. Furthermore, there was an inverse correlation between CLCA2 and FAK expression in 251 human breast cancer tissues. These results strongly suggest that CLCA2 is involved in the p53 tumor suppressor network and has a significant effect on cell migration and invasion.

DOI PubMed

DNA methylation and microRNA dysregulation in cancer

Hiromu Suzuki, Reo Maruyama, Eiichiro Yamamoto, Masahiro Kai

MOLECULAR ONCOLOGY ( ELSEVIER SCI LTD ) 6 ( 6 ) 567 - 578 2012.12 [Refereed]

DNA methylation plays a key role in the silencing of numerous cancer-related genes, thereby affecting a number of vital cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion and angiogenesis. Also widely altered in human malignancies is the expression of microRNAs (miRNAs), a class of small noncoding RNAs that act as posttranscriptional regulators of gene expression. Furthermore, emerging evidence now supports the idea that DNA methylation is crucially involved in the dysregulation of miRNAs in cancer. This is in part the result of technological advances that enable more comprehensive analysis of miRNA expression profiles and the epigenome in cancer cells, which has led to the identification of a number of epigenetically regulated miRNAs. As with protein-coding genes, it appears that miRNA genes involved in regulating cancer-related pathways are silenced in association with CpG island hypermethylation. In addition, methylation in CpG island shore regions and DNA hypomethylation also appear to contribute to miRNA dysregulation in cancer. Aberrant DNA methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Moreover, re-expression of miRNAs and the replacement of tumor suppressive miRNAs using miRNA mimics or expression vectors could be effective approaches to cancer therapy. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI PubMed

Model of translational cancer research in multiple myeloma

Hiroshi Yasui, Tadao Ishida, Reo Maruyama, Masanori Nojima, Hiroshi Ikeda, Hiromu Suzuki, Toshiaki Hayashi, Yasuhisa Shinomura, Kohzoh Imai

Cancer Science 103 ( 11 ) 1907 - 1912 2012.11 [Refereed]

Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in multiple myeloma (MM). The introduction of novel agents such as the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, which were rapidly translated from preclinical studies at the Dana-Farber Cancer Institute into clinical trials, has changed the treatment paradigm and markedly extended overall survival MM has therefore become a remarkable example of translational cancer research in new drug development. In this article, with the aim of determining the key factors underlying success in translational research, we focus on our studies of MM at Dana-Farber Cancer Institute as well as at our institutes. The identification of these key factors will help to promote translational cancer research not only in MM but also in other hematologic malignancies and solid tumors, to develop novel therapies, to overcome drug resistance, and to thereby improve the prognosis of cancer patients. © 2012 Japanese Cancer Association.

DOI PubMed

Molecular Dissection of Premalignant Colorectal Lesions Reveals Early Onset of the CpG Island Methylator Phenotype

Eiichiro Yamamoto, Hiromu Suzuki, Hiro-o Yamano, Reo Maruyama, Masanori Nojima, Seiko Kamimae, Takeshi Sawada, Masami Ashida, Kenjiro Yoshikawa, Tomoaki Kimura, Ryo Takagi, Taku Harada, Ryo Suzuki, Akiko Sato, Masahiro Kai, Yasushi Sasaki, Takashi Tokino, Tamotsu Sugai, Kohzoh Imai, Yasuhisa Shinomura, Minoru Toyota

AMERICAN JOURNAL OF PATHOLOGY ( ELSEVIER SCIENCE INC ) 181 ( 5 ) 1847 - 1861 2012.11 [Refereed]

The concept of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) is widely accepted, although the timing of its occurrence and its interaction with other genetic defects are not fully understood. Our aim in this study was to unravel the molecular development of CIMP cancers by dissecting their genetic and epigenetic signatures in precancerous and malignant colorectal lesions. We characterized the methylation profile and BRAF/KRAS mutation status in 368 colorectal tissue samples, including precancerous and malignant lesions. In addition, genome-wide copy number aberrations, methylation profiles, and mutations of BRAF, KRAS, TP53, and PIR3CA pathway genes were examined in 84 colorectal lesions. Genome-wide methylation analysis of CpG islands and selected marker genes revealed that CRC precursor lesions are in three methylation subgroups: CIMP-high, CIMP-low, and CIMP-negative. Interestingly; a subset of GIMP-positive malignant lesions exhibited frequent copy number gains on chromosomes 7 and 19 and genetic defects in the AKT/PIK3CA pathway gems. Analysis of mixed lesions containing both precancerous and malignant components revealed that most aberrant methylation is acquired at the precursor stage, whereas copy number aberrations are acquired during the progression from precursor to malignant lesion. Our integrative genomic and epigenetic analysis suggests early onset of CIMP during CRC development and indicates a previously unknown CRC development pathway in which epigenetic instability associates with genomic alterations. (Am J Pathol 2012, 181:1847-1861; http://dx.doi.org/10.1016/j.ajpath.2012.08.007)

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Long noncoding RNA involvement in cancer

Reo Maruyama, Hiromu Suzuki

BMB REPORTS ( KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY ) 45 ( 11 ) 604 - 611 2012.11 [Refereed]

Recent advances in genome and transcriptome analysis have enabled identification of numerous members of a new class of noncoding RNA, long noncoding RNA (IncRNA). IncRNAs are broadly defined as RNA molecules greater than 200 nt in length and lacking an open reading frame. Recent studies provide evidence that IncRNAs play central roles in a wide range of cellular processes through interaction with key component proteins in the gene regulatory system, and that alteration of their cell- or tissue-specific expression and/or their primary or secondary structures is thought to promote cell proliferation, invasion and metastasis. The biological and molecular characteristics of the large majority of IncRNAs remains unknown, and it is anticipated that improved understanding of the roles played by IncRNAs in cancer will lead to the development of novel biomarkers and effective therapeutic strategies. [BMB Reports 2012; 45(11): 604-611]

DOI PubMed

Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma

Masahiro Shitani, Shigeru Sasaki, Noriyuki Akutsu, Hideyasu Takagi, Hiromu Suzuki, Masanori Nojima, Hiroyuki Yamamoto, Takashi Tokino, Koichi Hirata, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

TUMOR BIOLOGY ( SPRINGER ) 33 ( 5 ) 1307 - 1317 2012.10 [Refereed]

Aberrant DNA methylation has been implicated in the development of hepatocellular carcinoma (HCC). Our aim was to clarify its molecular mechanism and to identify useful biomarkers by screening for DNA methylation in HCC. Methylated CpG island amplification coupled with CpG island microarray (MCAM) analysis was carried out to screen for methylated genes in primary HCC specimens [hepatitis B virus (HBV)-positive, n = 4; hepatitis C virus (HCV)-positive, n = 5; HBV/HCV-negative, n = 7]. Bisulfite pyrosequencing was used to analyze the methylation of selected genes and long interspersed nuclear element (LINE)-1 in HCC tissue (n = 57) and noncancerous liver tissue (n = 50) from HCC patients and in HCC cell lines (n = 10). MCAM analysis identified 332, 342, and 259 genes that were methylated in HBV-positive, HCV-positive, and HBV/HCV-negative HCC tissues, respectively. Among these genes, methylation of KLHL35, PAX5, PENK, and SPDYA was significantly higher in HCC tissue than in noncancerous liver tissue, irrespective of the hepatitis virus status. LINE-1 hypomethylation was also prevalent in HCC and correlated positively with KLHL35 and SPDYA methylation. Receiver operating characteristic curve analysis revealed that methylation of the four genes and LINE-1 strongly discriminated between HCC tissue and noncancerous liver tissue. Our data suggest that aberrant hyper- and hypomethylation may contribute to a common pathogenesis mechanism in HCC. Hypermethylation of KLHL35, PAX, PENK, and SDPYA and hypomethylation of LINE-1 could be useful biomarkers for the detection of HCC.

DOI PubMed

Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer

Hiroyuki Takamaru, Eiichiro Yamamoto, Hiromu Suzuki, Masanori Nojima, Reo Maruyama, Hiro-o Yamano, Kenjiro Yoshikawa, Tomoaki Kimura, Taku Harada, Masami Ashida, Ryo Suzuki, Hiroyuki Yamamoto, Masahiro Kai, Takashi Tokino, Tamotsu Sugai, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

CANCER PREVENTION RESEARCH ( AMER ASSOC CANCER RESEARCH ) 5 ( 10 ) 1203 - 1212 2012.10 [Refereed]

Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer. Cancer Prev Res; 5(10); 1203-12. (c) 2012 AACR.

DOI PubMed

DNAメチル化の網羅的解析により同定された新規肝癌関連遺伝子

志谷真啓, 鈴木拓, 阿久津典之, 高木秀安, 佐々木茂, 野島正寛, 山本博幸, 時野隆至, 平田公一, 篠村恭久

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 109 ( 臨増大会 ) A700 - A700 2012.09

PLC/PRF/5細胞株におけるB型肝炎ウイルスDNAの新しい検出法

平石哲也, 渡邊嘉行, 及川律子, 山田典栄, 奥瀬千晃, 鈴木拓, 四柳宏, 鈴木通博, 伊東文生

日本分子腫瘍マーカー研究会プログラム・講演抄録 ( 日本分子腫瘍マーカー研究会 ) 32回 72 - 72 2012.09

多発性骨髄腫におけるトランスレーショナルリサーチの試み(A model of translational cancer research in multiple myeloma)

安井寛, 石田禎夫, 青木由佳, 丸山玲緒, 野島正寛, 池田博, 鈴木拓, 林敏昭, 篠村恭久, 今井浩三

日本癌学会総会記事 ( (一社)日本癌学会 ) 71回 301 - 301 2012.08

多発性骨髄腫の発生におけるDNAメチロームの意義 MBDシーケンシング法によるアプローチ(The significance of DNA methylome for tumor progression in multiple myeloma: An MBD-sequencing-based approach)

野島正寛, 青木由佳, 安井寛, 丸山玲緒, 麻奥英毅, 石田禎夫, 時野隆至, 森満, 鈴木拓, 篠村恭久

日本癌学会総会記事 ( (一社)日本癌学会 ) 71回 385 - 385 2012.08

Cigarette smoking, alcohol consumption, and risk of systemic lupus erythematosus: A case-control study in a Japanese population

Chikako Kiyohara, Masakazu Washio, Takahiko Horiuchi, Toyoko Asami, Saburo Ide, Tatsuya Atsumi, Gen Kobashi, Yoshifumi Tada, Hiroki Takahashi, Hiroko Kodama, Koichi Akashi, Mine Harada, Hiroaki Niiro, Hiroshi Tsukamoto, Takao Hotokebuchi, Kohei Nagasawa, Osamu Ushiyama, Mitsuru Mori, Asae Oura, Yasuhisa Sinomura, Hiromu Suzuki, Motohisa Yamamoto, Tetsuya Horita, Takao Koike, Takashi Abe, Hisato Tanaka, Norihiko Nogami, Kazushi Okamoto, Naomasa Sakamoto, Satoshi Sasaki, Yoshihiro Miyake, Tetsuji Yokoyama, Yoshio Hirota, Yutaka Inaba, Masaki Nagai

Journal of Rheumatology 39 ( 7 ) 1363 - 1370 2012.07 [Refereed]

Objective. Cigarette smoking may be associated with increased risk of systemic lupus erythematosus (SLE), whereas the role of alcohol consumption is unknown. We examined the association between SLE risk and smoking or drinking. Methods. We investigated the relationship of smoking and drinking compared to SLE risk among 171 SLE cases and 492 healthy controls in female Japanese subjects. Unconditional logistic regression was used to compute OR and 95% CI, with adjustments for several covariates. Results. Compared with nonsmoking, current smoking was significantly associated with increased risk of SLE (OR 3.06, 95% CI 1.86-5.03). The higher the level of exposure to cigarette smoke, the higher the risk of SLE. Inhalation was also associated with increased SLE risk (OR 3.73, 95% CI 1.46-9.94 for moderate inhalation OR 3.06, 95% CI 1.81-5.15 for deep inhalation). In contrast, light/moderate alcohol consumption had a protective effect on SLE risk (OR 0.38, 95% CI 0.19-0.76). As for beer, the risks for non-beer drinkers and beer drinkers were similar. This also applies to alcoholic beverages other than beer. Conclusion. Our results suggest that smoking was positively associated with increased SLE risk whereas light/moderate alcohol consumption was inversely associated with SLE risk, irrespective of the type of alcoholic beverage. Additional studies are warranted to confirm these findings. The Journal of Rheumatology Copyright © 2012. All rights reserved.

DOI PubMed

Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer

Hiroyuki Yamamoto, Yasushi Adachi, Hiroaki Taniguchi, Hiroaki Kunimoto, Katsuhiko Nosho, Hiromu Suzuki, Yasuhisa Shinomura

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBLISHING GROUP INC ) 18 ( 22 ) 2745 - 2755 2012.06 [Refereed]

There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of mR-155 has been shown to downreijulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets. (C) 2012 Baishideng. All rights reserved.

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Hypermethylation of Sox17 gene is useful as a molecular diagnostic application in early gastric cancer

Yoshichika Oishi, Yoshiyuki Watanabe, Yoshihito Yoshida, Yoshinori Sato, Tetsuya Hiraishi, Ritsuko Oikawa, Tadateru Maehata, Hiromu Suzuki, Minoru Toyota, Hirohumi Niwa, Michihiro Suzuki, Fumio Itoh

TUMOR BIOLOGY ( SPRINGER ) 33 ( 2 ) 383 - 393 2012.04 [Refereed]

Although minimal invasive treatment is widely accepted in the early stages of gastric cancer (GCa), we still do not have any appropriate risk markers to detect residual neoplasia and the potential for recurrence. We previously reported that aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for the detection of gastric neoplasia. Our goal is to find and identify some candidate genes, using genome-wide DNA methylation analysis, as a treatment marker for early gastric cancer (EGC). We performed methylated CpG island amplification microarray analysis using 12 gastric washes (six each of pre- and post-endoscopic treatment in each of the same patients). We finally focused on Sox17 gene. We examined the DNA methylation status of Sox17 in a validation set consisting of 128 wash samples (pre, 64; post, 64) at EGC. We next carried out functional studies to identify Sox17. Sox17 showed significant differential methylation between pre- and post-treatments in EGC patients (Sox17, p < 0.0001). Moreover, treating GCa cells that lacked Sox17 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Additionally, the introduction of exogenous Sox17 into silenced cells suppressed colony formation. Gastric wash-based DNA methylation analysis could be useful for early detection of recurrence following endoscopic resection in EGC patients. Our data suggest that the silencing of Sox17 occurs frequently in EGC and may play a key role in the development and progression of the disease.

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DNA methylation biomarker candidates for early detection of colon cancer

Joo Mi Yi, Mashaal Dhir, Angela A. Guzzetta, Christine A. Iacobuzio-Donahue, Kyu Heo, Kwang Mo Yang, Hiromu Suzuki, Minoru Toyota, Hwan-Mook Kim, Nita Ahuja

TUMOR BIOLOGY ( SPRINGER ) 33 ( 2 ) 363 - 372 2012.04 [Refereed]

Promoter CpG island hypermethylation of tumor suppressor genes is a common hallmark of all human cancers. Many researchers have been looking for potential epigenetic therapeutic targets in cancer using gene expression profiling with DNA microarray approaches. Our recent genome-wide platform of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that FBN2 and TCERG1L gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. In this study, promoter DNA hypermethylation of FBN2 and TCERG1L in CRC occurs as an early and cancer-specific event in colorectal cancer. Both genes showed high frequency of methylation in colon cancer cell lines (> 80% for both of genes), adenomas (77% for FBN2, 90% for TCERG1L, n = 39), and carcinomas (86% for FBN2, 99% for TCERG1L, n = 124). Bisulfite sequencing confirmed cancer-specific methylation of FBN2 and TCERG1L of promoters in colon cancer cell line and cancers but not in normal colon. Methylation of FBN2 and TCERG1L is accompanied by downregulation in cell lines and in primary tumors as described in the Oncomine (TM) website. Together, our results suggest that gene silencing of FBN2 and TCERG1L is associated with promoter DNA hypermethylation in CRC tumors and may be excellent biomarkers for the early detection of CRC.

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