Details of a Researcher - SUZUKI Hiromu

Papers - SUZUKI Hiromu

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Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer

Ying Su, Ashim Subedee, Noga Bloushtain-Qimron, Virginia Savova, Marcin Krzystanek, Lewyn Li, Andriy Marusyk, Doris P. Tabassum, Alexander Zak, Mary Jo Flacker, Mei Li, Jessica J. Lin, Saraswati Sukumar, Hiromu Suzuki, Henry Long, Zoltan Szallasi, Alexander Gimelbrant, Reo Maruyama, Kornelia Polyak

CELL REPORTS ( CELL PRESS ) 11 ( 10 ) 1549 - 1563 2015.06 [Refereed]

Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells.

Molecular analysis of isolated tumor glands from endometrial endometrioid adenocarcinomas

Yasuko Suga, Tamotsu Sugai, Noriyuki Uesugi, Tomonori Kawasaki, Tomoyuki Fukagawa, Eiichiro Yamamoto, Kazuyuki Ishida, Hiromu Suzuki, Toru Sugiyama

PATHOLOGY INTERNATIONAL ( WILEY-BLACKWELL ) 65 ( 5 ) 240 - 249 2015.05 [Refereed]

We studied the extensive molecular alterations of endometrial endometrioid adenocarcinoma (EEA) using a crypt isolation method. We analyzed copy number variation (CNV) using a single nucleotide polymorphism (SNP) array, genetic mutations (KRAS, BRAF, p53, PIK3CA), DNA methylation and microsatellite instability (MSI) status. In addition, loss of PTEN protein expression was examined. Increased chromosome copy numbers of 1q21.2-44 (22%) and 10q11.21-23.31 (28%) were seen relatively frequently in EEA, and copy-neutral loss of heterozygosity (LOH) was also observed in 10q22.1-26.3 (22%). The CNV patterns of EEA were classified into four groups through hierarchical cluster analysis. Cluster 1 had many CNVs of 10q, and cluster 2 was characterized by MSI status. In cluster 3, increased CNVs of 1q were often seen. In cluster 4, p53 mutations were detected. KRAS and PIK3CA mutations and reduced PTEN protein expression were common to all groups. On the other hand, CpG island methylator phenotype (CIMP) was rare in all groups. The data indicated an association with chromosomal gain of 1q and 10q or 10q copy-neutral LOH in some cases. We suggest that EEA consists of four groups that are characterized with molecular alterations.

[Endoscopic diagnosis and clinical management for serrated lesions of the large intestine].

Yamano HO, Tanaka Y, Matsushita HO, Yoshikawa K, Takagi R, Harada E, Nakaoka M, Himori R, Yoshida Y, Tanaka D, Sato K, Imai Y, Sugai T, Eizuka M, Yamamoto E, Aoki H, Suzuki H

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 112 ( 4 ) 676 - 682 2015.04 [Refereed] [Domestic journal]

Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis

Kei Mitsuhashi, Katsuhiko Nosho, Yasutaka Sukawa, Yasutaka Matsunaga, Miki Ito, Hiroyoshi Kurihara, Shinichi Kanno, Hisayoshi Igarashi, Takafumi Naito, Yasushi Adachi, Mami Tachibana, Tokuma Tanuma, Hiroyuki Maguchi, Toshiya Shinohara, Tadashi Hasegawa, Masafumi Imamura, Yasutoshi Kimura, Koichi Hirata, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura

ONCOTARGET ( IMPACT JOURNALS LLC ) 6 ( 9 ) 7209 - 7220 2015.03 [Refereed]

Recently, bacterial infection causing periodontal disease has attracted considerable attention as a risk factor for pancreatic cancer. Fusobacterium species is an oral bacterial group of the human microbiome. Some evidence suggests that Fusobacterium species promote colorectal cancer development; however, no previous studies have reported the association between Fusobacterium species and pancreatic cancer. Therefore, we examined whether Fusobacterium species exist in pancreatic cancer tissue. Using a database of 283 patients with pancreatic ductal adenocarcinoma (PDAC), we tested cancer tissue specimens for Fusobacterium species. We also tested the specimens for KRAS, NRAS, BRAF and PIK3CA mutations and measured microRNA-21 and microRNA-31. In addition, we assessed epigenetic alterations, including CpG island methylator phenotype (CIMP). Our data showed an 8.8% detection rate of Fusobacterium species in pancreatic cancers; however, tumor Fusobacterium status was not associated with any clinical and molecular features. In contrast, in multivariate Cox regression analysis, compared with the Fusobacterium species- negative group, we observed significantly higher cancer-specific mortality rates in the positive group (p = 0.023). In conclusion, Fusobacterium species were detected in pancreatic cancer tissue. Tumor Fusobacterium species status is independently associated with a worse prognosis of pancreatic cancer, suggesting that Fusobacterium species may be a prognostic biomarker of pancreatic cancer.

Clinicopathological and Molecular Characteristics of Serrated Lesions in Japanese Elderly Patients

Katsuhiko Nosho, Hisayoshi Igarashi, Miki Ito, Kei Mitsuhashi, Hiroyoshi Kurihara, Shinichi Kanno, Shinji Yoshii, Masashi Mikami, Hiroaki Takahashi, Takaya Kusumi, Masao Hosokawa, Yasutaka Sukawa, Yasushi Adachi, Tadashi Hasegawa, Kenji Okita, Koichi Hirata, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura

DIGESTION ( KARGER ) 91 ( 1 ) 57 - 63 2015 [Refereed]

Background: The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. Methods: In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA-31 (miR-31). Results: The frequency of elderly patients (aged >= 75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. Conclusion: In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential. (C) 2015 S. Karger AG, Basel

Dietary patterns and the risk of systemic lupus erythematosus in a Japanese population: The Kyushu Sapporo SLE (KYSS) Study

Kiyohara C, Washio M, Horiuchi T, Takahashi H, Tada Y, Kobashi G, Asami T, Ide S, Atsumi T, Kodama H, Akashi K, Harada M, Tsukamoto H, Hotokebuchi T, Nagasawa K, Ushiyama O, Mori M, Oura A, Sinomura Y, Suzuki H, Yamamoto M, Abe T, Tanaka H, Yasuda S, Nogami N, Okamoto K, Sakamoto N, Sasaki S, Miyake Y, Yokoyama T, Inaba Y, Nagai M

International Medical Journal 22 ( 3 ) 110 - 115 2015 [Refereed]

MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions

Miki Ito, Kei Mitsuhashi, Hisayoshi Igarashi, Katsuhiko Nosho, Takafumi Naito, Shinji Yoshii, Hiroaki Takahashi, Masahiro Fujita, Yasutaka Sukawa, Eiichiro Yamamoto, Taiga Takahashi, Yasushi Adachi, Masanori Nojima, Yasushi Sasaki, Takashi Tokino, Yoshifumi Baba, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura

INTERNATIONAL JOURNAL OF CANCER ( WILEY-BLACKWELL ) 135 ( 11 ) 2507 - 2515 2014.12 [Refereed]

The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p=0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum.

Biological significance of the CpG island methylator phenotype

Hiromu Suzuki, Eiichiro Yamamoto, Reo Maruyama, Takeshi Niinuma, Masahiro Kai

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 455 ( 1-2 ) 35 - 42 2014.12 [Refereed]

Cancers exhibiting the CpG island methylator phenotype (CIMP) are found among a wide variety of human malignancies and represent a subclass of tumors showing concurrent hypermethylation of multiple CpG islands. These CIMP-positive tumors often exhibit characteristic molecular and clinicopathological features, suggesting CIMP represents a distinct carcinogenic pathway. However, marker genes to define CIMP have been largely inconsistent among studies, which has caused results to vary. Nonetheless, recent advances in genome-wide methylation analysis have enabled the existence of CIMP to be confirmed, and large-scale cancer genome analyses have begun to unravel the previously unknown molecular basis of CIMP tumors. CIMP is strongly associated with clinical outcome, suggesting it may be a predictive biomarker. (C) 2014 Elsevier Inc. All rights reserved.

Targeting of miR34a-NOTCH1 Axis Reduced Breast Cancer Stemness and Chemoresistance

Eun Young Park, EunSun Chang, Eun Ji Lee, Hyun-Woo Lee, Hyeok-Gu Kang, Kyung-Hee Chun, Yu Mi Woo, Hyun Kyung Kong, Je Yeong Ko, Hiromu Suzuki, Erwei Song, Jong Hoon Park

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 74 ( 24 ) 7573 - 7582 2014.12 [Refereed]

Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stemcell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment. (C)2014 AACR.

Analysis of DNA Methylation in Bowel Lavage Fluid for Detection of Colorectal Cancer

Taku Harada, Eiichiro Yamamoto, Hiro-o Yamano, Masanori Nojima, Reo Maruyama, Kohei Kumegawa, Masami Ashida, Kenjiro Yoshikawa, Tomoaki Kimura, Eiji Harada, Ryo Takagi, Yoshihito Tanaka, Hironori Aoki, Masayo Nishizono, Michiko Nakaoka, Akihiro Tsuyada, Takeshi Niinuma, Masahiro Kai, Kazuya Shimoda, Yasuhisa Shinomura, Tamotsu Sugai, Kohzoh Imai, Hiromu Suzuki

CANCER PREVENTION RESEARCH ( AMER ASSOC CANCER RESEARCH ) 7 ( 10 ) 1002 - 1010 2014.10 [Refereed]

Aberrant DNA methylation could potentially serve as a biomarker for colorectal neoplasms. In this study, we assessed the feasibility of using DNA methylation detected in bowel lavage fluid (BLF) for colorectal cancer screening. A total of 508 BLF specimens were collected from patients with colorectal cancer (n = 56), advanced adenoma (n = 53), minor polyp (n = 209), and healthy individuals (n = 190) undergoing colonoscopy. Methylation of 15 genes (miR-1-1, miR-9-1, miR-9-3, miR-34b/c, miR-124-1, miR-124-2, miR-124-3, miR-137, SFRP1, SFRP2, APC, DKK2, WIF1, LOC386758, and ZNF582) was then analyzed in MethyLight assays, after which receiver operating characteristic (ROC) curves were analyzed to assess the diagnostic performance of BLF methylation. Through analyzing BLF specimens in a training set (n = 345), we selected the three genes showing the greatest sensitivity for colorectal cancer detection (miR-124-3, 71.8%; LOC386758, 79.5%; and SFRP1, 74.4%). A scoring system based on the methylation of those three genes (M-score) achieved 82% sensitivity and 79% specificity, and the area under the ROC curve (AUC) was 0.834. The strong performance of this system was then validated in an independent test set (n = 153; AUC = 0.808). No significant correlation was found between M-score and the clinicopathologic features of the colorectal cancers. Our results demonstrate that DNA methylation in BLF specimens may be a useful biomarker for the detection of colorectal cancer. (C) 2014 AACR.

Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis

Yoko Takaki, Yoshimasa Saito, Azusa Takasugi, Kohta Toshimitsu, Shoji Yamada, Toshihide Muramatsu, Masaki Kimura, Kazuo Sugiyama, Hiromu Suzuki, Eri Arai, Hidenori Ojima, Yae Kanai, Hidetsugu Saito

CANCER SCIENCE ( WILEY-BLACKWELL ) 105 ( 10 ) 1254 - 1260 2014.10 [Refereed]

Non-alcoholic steatohepatitis (NASH) has emerged as a common cause of chronic liver disease and virus-independent hepatocellular carcinoma (HCC) in patients with obesity, diabetes, and metabolic syndrome. To reveal the molecular mechanism underlying hepatocarcinogenesis from NASH, microRNA (miRNA) expression profiles were analyzed in STAM mice, a NASH-HCC animal model. MicroRNA expression was also examined in 42 clinical samples of HCC tissue. Histopathological images of the liver of STAM mice at the ages of 6, 8, 12, and 18weeks showed findings compatible with fatty liver, NASH, liver cirrhosis (LC), and HCC, respectively. Expression of miR-122 in non-tumor LC at the age of 18weeks was significantly lower than that in LC at the age of 12weeks. Expression of miR-122 was further decreased in HCCs relative to non-tumor LC at the age of 18weeks. Expression of miR-122 was also decreased in clinical samples of liver tissue showing macrovesicular steatosis and HCC, being consistent with the findings in the NASH model mice. DNA methylation analysis revealed that silencing of miR-122 was not mediated by DNA hypermethylation of the promoter region. These results suggest that silencing of miR-122 is an early event during hepatocarcinogenesis from NASH, and that miR-122 could be a novel molecular marker for evaluating the risk of HCC in patients with NASH.

MicroRNA-31 expression in colorectal serrated pathway progression

Hironori Aoki, Katsuhiko Nosho, Hisayoshi Igarashi, Miki Ito, Kei Mitsuhashi, Takafumi Naito, Eiichiro Yamamoto, Tokuma Tanuma, Masafumi Nomura, Hiroyuki Maguchi, Toshiya Shinohara, Hiromu Suzuki, Hiroyuki Yamamoto, Yasuhisa Shinomura

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBLISHING GROUP INC ) 20 ( 34 ) 12346 - 12349 2014.09 [Refereed]

MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers (CRC). We have recently observed that microRNA-31 (miR-31) expression is associated with BRAF mutation and prognosis in CRC. Moreover, high miR-31 expression is frequently detected in sessile serrated adenomas compared with hyperplastic polyps (HPs). These results suggest that miR-31 may contribute to the progression of serrated lesions. At a follow-up colonoscopy, we observed the case of a 75-year-old man with a 7-mm flat-elevated lesion in the cecum and diagnosed the lesion as an early invasive carcinoma with serrated features. Tissue specimens were obtained from the representative areas to compare the molecular alterations in the carcinoma component with those in the HP component. Higher miR-31 expression was observed in the carcinoma component (57-fold increase) and the HP component (8-fold increase) compared with the paired normal mucosa, suggesting that miR-31 may be one of the key molecules in serrated pathway progression. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Array-based genome-wide RNAi screening to identify shRNAs that enhance p53-related apoptosis in human cancer cells

Masashi Idogawa, Tomoko Ohashi, Jun Sugisaka, Yasushi Sasaki, Hiromu Suzuki, Takashi Tokino

ONCOTARGET ( IMPACT JOURNALS LLC ) 5 ( 17 ) 7540 - 7548 2014.09 [Refereed]

p53 transduction is a potentially effective cancer therapy but does not result in a good therapeutic response in all human cancers due to resistance to apoptosis. To discover factors that overcome resistance to p53-induced apoptosis, we attempted to identify RNAi sequences that enhance p53-induced apoptosis. We screened a genome-wide lentiviral shRNA library in liver cancer Huh-7 and pancreatic cancer Panc-1 cells, both of which resist p53-induced apoptosis. After the infection of adenovirus expressing p53 or LacZ as a control, shRNA-treated populations were analyzed by microarray. We identified shRNAs that were significantly decreased in p53-infected cells compared with control cells. Among these shRNAs, shRNA-58335 was markedly decreased in both cancer cell lines tested. shRNA-58335 enhanced p53-related apoptosis in vitro and augmented the inhibitory effect of adenoviral p53 transduction on tumor growth in vivo. Furthermore, the enhanced apoptotic response by shRNA-58335 was also confirmed by treatment with PRIMA-1, which reactivates mutant p53, instead of adenoviral p53 transduction. We found that shRNA-58335 evokes the apoptotic response following p53 transduction or functional restoration of p53 with a small molecule drug in cancer cells resistant to p53-induced apoptosis. The combination of p53 restoration and RNAi-based drugs is expected to be a promising novel cancer therapy.

半導体シーケンサーを用いたがん関連遺伝子の網羅的解析(Comprehensive genomic analyses of cancer tissues by semiconductor-based next-generation sequencing)

佐々木泰史, 中垣貴文, 田村みゆき, 竹田康佑, 井戸川雅史, 大箸智子, 鈴木拓, 篠村恭久, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 73回 P - 2146 2014.09

口腔扁平上皮癌の発生や進展において重要な役割を果たす長鎖非コードRNAの同定(Identification of long non-coding RNAs potentially involved in oral squamous cell carcinoma)

西山廣陽, 丸山玲緒, 竹田康佑, 中垣貴文, 新沼猛, 荻和弘, 出張裕也, 甲斐正広, 宮崎晃亘, 佐々木泰史, 時野隆至, 平塚博義, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 73回 P - 3277 2014.09

IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

Takafumi Naito, Katsuhiko Nosho, Miki Ito, Hisayoshi Igarashi, Kei Mitsuhashi, Shinji Yoshii, Hironori Aoki, Masafumi Nomura, Yasutaka Sukawa, Eiichiro Yamamoto, Yasushi Adachi, Hiroaki Takahashi, Masao Hosokawa, Masahiro Fujita, Toshinao Takenouchi, Reo Maruyama, Hiromu Suzuki, Yoshifumi Baba, Kohzoh Imai, Hiroyuki Yamamoto, Shuji Ogino, Yasuhisa Shinomura

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBLISHING GROUP INC ) 20 ( 29 ) 10050 - 10061 2014.08 [Refereed]

AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions. METHODS: To accurately analyze the association between the histological types and molecular features of each type of serrated lesion, we consecutively collected 1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types [hyperplastic polyps (HPs, n = 121), sessile serrated adenomas (SSAs, n = 132), traditional serrated adenomas (TSAs, n = 111), non-serrated adenomas (n = 195), and colorectal cancers (CRCs, n = 827)]. We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1 (LINE-1) in HPs (n = 115), SSAs (n = 120), SSAs with cytological dysplasia (n = 10), TSAs (n = 91), TSAs with high-grade dysplasia (HGD) (n = 15), non-serrated adenomas (n = 80), non-serrated adenomas with HGD (n = 105), and CRCs (n = 794). For the accurate quantification of the relative methylation levels (scale 0%-100%) of IGF2 DMR0 and LINE-1, we used bisulfite pyrosequencing method. Tumor specimens were analyzed for microsatellite instability, KRAS (codons 12 and 13), BRAF (V600E), and PIK3CA (exons 9 and 20) mutations; MLH1 and MGMT methylation; and IGF2 expression by immunohistochemistry. RESULTS: The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas (with or without HGD) was as follows: mean 61.7, median 62.5, SD 18.0, range 5.0-99.0, interquartile range 49.5-74.4. The IGF2 DMR0 methylation level was divided into quartiles (Q1 >= 74.5, Q2 62.6-74.4, Q3 49.6-62.5, Q4 <= 49.5) for further analysis. With regard to the histological type, the IGF2 DMR0 methylation levels of SSAs (mean +/- SD, 73.1 +/- 12.3) were significantly higher than those of HPs (61.9 +/- 20.5), TSAs (61.6 +/- 19.6), and non-serrated adenomas (59.0 +/- 15.8) (P < 0.0001). The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level (r = -0.21, P = 0.0051). IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs, TSAs, and non-serrated adenomas (P < 0.0001). Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs (P < 0.0001). The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD (50.2 +/- 18.7 and 55.7 +/- 5.4, respectively) were significantly lower than those in TSAs (61.6 +/- 19.6 and 58.8 +/- 4.7, respectively) (IGF2 DMR0, P = 0.038; LINE-1, P = 0.024). CONCLUSION: IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway. Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Proteomic Analysis of Responsive Proteins Induced in Japanese Birch Plantlet Treated with Salicylic Acid.

Suzuki H, Takashima Y, Ishiguri F, Yoshizawa N, Yokota S

Proteomes 2 ( 3 ) 323 - 340 2014.07 [Refereed]

Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk

Ryo Suzuki, Eiichiro Yamamoto, Masanori Nojima, Reo Maruyama, Hiro-o Yamano, Kenjiro Yoshikawa, Tomoaki Kimura, Taku Harada, Masami Ashida, Takeshi Niinuma, Akiko Sato, Katsuhiko Nosho, Hiroyuki Yamamoto, Masahiro Kai, Tamotsu Sugai, Kohzoh Imai, Hiromu Suzuki, Yasuhisa Shinomura

JOURNAL OF GASTROENTEROLOGY ( SPRINGER JAPAN KK ) 49 ( 7 ) 1135 - 1144 2014.07 [Refereed]

Metachronous gastric cancer (GC) can develop after endoscopic resection of GC and cannot be predicted based on clinical signature. Aberrant DNA methylation in noncancerous gastric mucosa is strongly implicated in gastric carcinogenesis and could be a useful biomarker of GC risk. We evaluated the clinical utility of DNA methylation as a biomarker of metachronous GC risk. We carried out scheduled follow-up endoscopy in 129 patients after curative endoscopic resection of GC. Biopsy specimens were collected from noncancerous mucosa in the gastric antrum and body, after which quantitative methylation analysis of miR-34b/c, SFRP1, SFRP2, SFRP5, DKK2 and DKK3 was carried out using bisulfite pyrosequencing. The utility of the methylation for predicting the risk of metachronous GC development was assessed using Kaplan-Meier and Cox proportional hazards model analyses. During the follow-up period, 17 patients (13 %) developed metachronous GCs. The cumulative incidence of metachronous GC was significantly higher among patients with elevated miR-34b/c, SFRP2 and DKK2 methylation in their gastric body. MiR-34b/c showed the strongest association with the risk of metachronous GC, and the cumulative incidence of metachronous GC was much higher in the high-miR-34b/c-methylation group than the low-methylation group. Multivariate analysis adjusted for age, sex, H. pylori status and pathological findings showed miR-34b/c methylation in gastric body to be an independent predictor of metachronous GC risk. Our results suggest that methylation of miR-34b/c in the mucosa of the noncancerous gastric body may be a useful biomarker for predicting the risk of metachronous GC.

Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites

Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Reo Maruyama, Lisa Kashima, Hiromu Suzuki, Takashi Tokino

HUMAN MOLECULAR GENETICS ( OXFORD UNIV PRESS ) 23 ( 11 ) 2847 - 2857 2014.06 [Refereed]

p53 is one of the most important known tumor suppressor genes, and it is inactivated in approximately half of human cancers. p53 family members execute various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. Therefore, the direct transcriptional targets of the p53 family must be explored to elucidate the functional mechanisms of family members. To identify the direct transcriptional targets of p53 family members, we performed chromatin immunoprecipitation together with next-generation sequencing (ChIP-seq) and searched for p53-binding motifs across the entire human genome. Among the identified ChIP-seq peaks, approximately half were located in an intergenic region. Therefore, we assumed large intergenic non-coding RNAs (lincRNAs) to be major targets of the p53 family. Recent reports have revealed that lincRNAs play an important role in various biological and pathological processes, such as development, differentiation, stemness and carcinogenesis. Through a combination of ChIP-seq and in silico analyses, we found 23 lincRNAs that are upregulated by the p53 family. Additionally, knockdown of specific lincRNAs modulated p53-induced apoptosis and promoted the transcription of a gene cluster. Our results suggest that p53 family members, and lincRNAs constitute a complex transcriptional network involved in various biological functions and tumor suppression.

Mesenchymal Stem Cells Cancel Azoxymethane-Induced Tumor Initiation

Masanao Nasuno, Yoshiaki Arimura, Kanna Nagaishi, Hiroyuki Isshiki, Kei Onodera, Suguru Nakagaki, Shuhei Watanabe, Masashi Idogawa, Kentaro Yamashita, Yasuyoshi Naishiro, Yasushi Adachi, Hiromu Suzuki, Mineko Fujimiya, Kohzoh Imai, Yasuhisa Shinomura

STEM CELLS ( WILEY-BLACKWELL ) 32 ( 4 ) 913 - 925 2014.04 [Refereed]

The role of mesenchymal stem cells (MSCs) in tumorigenesis remains controversial. Therefore, our goal was to determine whether exogenous MSCs possess intrinsic antineoplastic or proneoplastic properties in azoxymethane (AOM)-induced carcinogenesis. Three in vivo models were studied: an AOM/dextran sulfate sodium colitis-associated carcinoma model, an aberrant crypt foci model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). We also performed in vitro coculture experiments. As a result, we found that MSCs partially canceled AOM-induced tumor initiation but not tumor promotion. Moreover, MSCs inhibited the AARGC in colonic epithelial cells because of the removal of O-6-methylguanine (O(6)MeG) adducts through O(6)MeG-DNA methyltransferase activation. Furthermore, MSCs broadly affected the cell-cycle machinery, potentially leading to G1 arrest in vivo. Coculture of IEC-6 rat intestinal cells with MSCs not only arrested the cell cycle at the G1 phase, but also induced apoptosis. The anti-carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)-beta signaling because such properties were completely abrogated by absorption of TGF-beta under indirect coculture conditions. MSCs inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped from the AARGC. Furthermore, tumor initiation perturbed by MSCs might potentially dysregulate WNT and TGF-beta-Smad signaling pathways in subsequent tumorigenesis. Obtaining a better understanding of MSC functions in colon carcinogenesis is essential before commencing the broader clinical application of promising MSC-based therapies for cancer-prone patients with inflammatory bowel disease. Stem Cells 2014;32:913-925

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