Details of a Researcher - SUZUKI Hiromu

Papers - SUZUKI Hiromu

Division display 141 - 160 of about 344 ／ All the affair displays >>

Epigenetic activation of LY6K predicts the presence of metastasis and poor prognosis in breast carcinoma

Hyun Kyung Kong, Sae Jeong Park, Ye Sol Kim, Kyoung Min Kim, Hyun-Woo Lee, Hyeok-Gu Kang, Yu Mi Woo, Eun Young Park, Je Yeong Ko, Hiromu Suzuki, Kyung-Hee Chun, Erwei Song, Kyu Yun Jang, Jong Hoon Park

ONCOTARGET ( IMPACT JOURNALS LLC ) 7 ( 34 ) 55677 - 55689 2016.08 [Refereed]

The role of lymphocyte antigen 6 complex, locus K (LY6K) in breast cancer has been studied, whereas the epigenetic control of LY6K transcription is not fully understood. Here, we report that breast cancer patients with increased LY6K expression had shorter disease-free and overall survival than the patients with low levels of LY6K by multivariate analysis. LY6K also was upregulated in breast cancer patients with distant metastases than those without distant metastases, downregulating E-cadherin expression. Furthermore, xenograft tumor volumes from LY6K knockdown nude mice were reduced than those of mice treated with control lentivirus. Interestingly, LY6K has a CpG island (CGI) around the transcription start site and non-CGI in its promoter, called a CGI shore. LY6K expression was inversely correlated with methylation in not only CGI but CGI shore, which are associated with histone modifications. Additionally, LY6K methylation was increased by the PAX3 transcription factor due to the SNP242 mutation in LY6K CGI shore. Taken together, breast cancer risk and metastasis were significantly associated with not only LY6K expression, but also methylation of CGI shore which induced by SNP242 mutation. Our results suggest that an understanding epigenetic mechanism of the LY6K gene may be useful to diagnose carcinogenic risk and predict outcomes of patients with metastatic breast cancer.

Plasticity of lung cancer stem-like cells is regulated by the transcription factor HOXA5 that is induced by oxidative stress

Hiroshi Saijo, Yoshihiko Hirohashi, Toshihiko Torigoe, Ryota Horibe, Akari Takaya, Aiko Murai, Terufumi Kubo, Toshimitsu Kajiwara, Tsutomu Tanaka, Yosuke Shionoya, Eri Yamamoto, Reo Maruyama, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Yasuaki Tamura, Yasushi Sasaki, Takashi Tokino, Hiromu Suzuki, Toru Kondo, Hiroki Takahashi, Noriyuki Sato

ONCOTARGET ( IMPACT JOURNALS LLC ) 7 ( 31 ) 50043 - 50056 2016.08 [Refereed]

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are reasonable targets for cancer therapy. However, recent studies have revealed that some non-CSCs/CICs have plastic ability and can dedifferentiate into CSCs/CICs. Therefore, an understanding of the molecular mechanisms that control the plasticity is essential to achieve CSC/CIC-targeting therapy. In this study, we analyzed the plasticity of lung cancer cells and found that lung non-CSCs/CICs can dedifferentiate into CSCs/CICs in accordance with the expression of stem cell transcription factor SOX2. SOX2 expression was induced by the transcription factor HOXA5. Oxidative stress repressed the expression of HDAC8 and then induced histone 3 acetylation and increased the expression of HOXA5 and SOX2. These findings indicate that lung cancer cells have plasticity under a condition of oxidative stress and that HOAX5 has a critical role in dedifferentiation.

Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

Shohei Honda, Masashi Minato, Hiromu Suzuki, Masato Fujiyoshi, Hisayuki Miyagi, Masayuki Haruta, Yasuhiko Kaneko, Kanako C. Hatanaka, Eiso Hiyama, Takehiko Kamijo, Tadao Okada, Akinobu Taketomi

CANCER SCIENCE ( WILEY-BLACKWELL ) 107 ( 6 ) 812 - 819 2016.06 [Refereed]

Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome-wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180, MST1R, OCIAD2, and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event-free survival. These findings indicate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.

Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations

Takeshi Sawada, Eiichiro Yamamoto, Hiro-o Yamano, Masanori Nojima, Taku Harada, Reo Maruyama, Masami Ashida, Hironori Aoki, Hiro-o Matsushita, Kenjiro Yoshikawa, Eiji Harada, Yoshihito Tanaka, Shigenori Wakita, Takeshi Niinuma, Masahiro Kai, Makoto Eizuka, Tamotsu Sugai, Hiromu Suzuki

ONCOTARGET ( IMPACT JOURNALS LLC ) 7 ( 23 ) 35106 - 35118 2016.06 [Refereed]

To clarify the molecular and clinicopathological characteristics of colorectal serrated lesions, we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF-mutant precancerous lesions from 94 individuals. We then compared those results with the lesions' clinicopathological features, especially colorectal subsites. The lesions included hyperplastic polyps (n = 16), traditional serrated adenomas (TSAs) (n = 15), TSAs with sessile serrated adenomas (SSAs) (n = 6), SSAs (n = 49) and SSAs with dysplasia (n = 16). The prevalence of lesions exhibiting the CpG island methylator phenotype (CIMP) was lower in the sigmoid colon and rectum than in other bowel subsites, including the cecum, ascending, transverse and descending colon. In addition, several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum. These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location, histological findings and neoplastic pathways. By contrast, no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites, which may indicate the absence of an epigenetic field defect.

A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer

Kohei Kumegawa, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, Hiroshi Kitajima, Akihiro Tsuyada, Takeshi Niinuma, Masahiro Kai, Hiro-o Yamano, Tamotsu Sugai, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Hiromu Suzuki

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP ) 6 26699 2016.05 [Refereed]

Long noncoding RNAs (lncRNAs) have emerged as key components in multiple cellular processes, although their physiological and pathological functions are not fully understood. To identify cancer-related lncRNAs, we screened for those that are epigenetically silenced in colorectal cancer (CRC). Through a genome-wide analysis of histone modifications in CRC cells, we found that the transcription start sites (TSSs) of 1,027 lncRNA genes acquired trimethylation of histone H3 lysine 4 (H3K4me3) after DNA demethylation. Integrative analysis of chromatin signatures and the DNA methylome revealed that the promoter CpG islands (CGIs) of 66 lncRNA genes contained cancer-specific methylation. By validating the expression and methylation of lncRNA genes in CRC cells, we ultimately identified 20 lncRNAs, including ZNF582-AS1, as targets of epigenetic silencing in CRC. ZNF582-AS1 is frequently methylated in CRC cell lines (87.5%), primary CRCs (77.2%), colorectal adenomas (44.7%) and advanced adenomas (87.8%), suggesting that this methylation is an early event during colorectal tumorigenesis. Methylation of ZNF582-AS1 is associated with poor survival of CRC patients, and ectopic expression of ZNF582-AS1 suppressed colony formation by CRC cells. Our findings offer insight into the association between epigenetic alterations and lncRNA dysregulation in cancer and suggest that ZNF582-AS1 may be a novel tumor-suppressive lncRNA.

Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability-high phenotype

Ryo Sugimoto, Tamotsu Sugai, Wataru Habano, Masaki Endoh, Makoto Eizuka, Eiichiro Yamamoto, Noriyuki Uesugi, Kazuyuki Ishida, Tomonori Kawasaki, Takayuki Matsumoto, Hiromu Suzuki

INTERNATIONAL JOURNAL OF CANCER ( WILEY-BLACKWELL ) 138 ( 7 ) 1689 - 1697 2016.04 [Refereed]

The relevance of the clinicopathological and molecular features of early gastric cancers (EGCs) having the microsatellite instability (MSI)-high phenotype has not been clearly defined in sporadic gastric carcinogenesis. Here, we examined the clinicopathological and molecular characteristics of EGC according to MSI status in 330 patients with EGC (intestinal-type adenocarcinoma). Tumors were classified as MSI-high (45 cases), MSI-low (9 cases), or microsatellite stable (MSS; 276 cases). The specimens were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR-pyrosequencing to detect chromosomal allelic imbalances in multiple cancer-related chromosomal loci, MSI, gene mutations (KRAS and BRAF) and methylation status [high methylation epigenome (HME), intermediate methylation epigenome and low methylation epigenome]. In addition, the expression levels of various target proteins were examined using immunohistochemistry. Interestingly, EGC with the MSI phenotype showed distinct papillary features. The expression of gastric mucin was more frequent in EGC with the MSI phenotype, while p53 overexpression was common in EGCs, irrespective of MSI status. The frequency of HME was significantly higher in EGCs with the MSI phenotype than in EGCs with the MSS phenotype. Although there was a low frequency of allelic imbalance in EGCs with the MSI phenotype, some markers of allelic imbalance were more frequently detected in EGCs with the MSI-high phenotype than in EGCs with the MSS phenotype. KRAS and BRAF mutations were rare in EGCs. Thus, the MSI phenotype in EGC is a major precursor lesion in gastric cancer and is characterized by distinct clinicopathological and molecular features.

Relationship Between Noncoding RNA Dysregulation and Epigenetic Mechanisms in Cancer

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

LONG AND SHORT NONCODING RNAS IN CANCER BIOLOGY ( SPRINGER-VERLAG SINGAPORE PTE LTD ) 927 109 - 135 2016 [Refereed]

Epigenetic alterations, including aberrant DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, studies have demonstrated that short and long noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer, and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs act as tumor suppressors or oncogenes. In addition, emerging evidence suggests that dysregulation of long ncRNAs (lncRNAs) plays critical roles in tumorigenesis. And because ncRNAs are involved in regulating gene expression through interaction with epigenetic modifiers, their dysregulation appears causally related to epigenetic alterations in cancer. Dissection of the interrelationships between ncRNAs and epigenetic alterations has the potential to reveal novel approaches to the diagnosis and treatment of cancer.

【大腸鋸歯状病変の取り扱い】発生部位に基づいた大腸鋸歯状病変の臨床病理学的および分子病理学的検討

永塚真, 菅井有, 荒川典之, 高橋弥生, 杉本亮, 川崎啓祐, 梁井俊一, 中村昌太郎, 松下弘雄, 山野泰穂, 山本英一郎, 鈴木拓, 松本主之

胃と腸 ( (株)医学書院 ) 50 ( 13 ) 1709 - 1722 2015.12

左側と右側大腸間における大腸鋸歯状病変の臨床病理学的,分子遺伝学的検討を行った.対象として左側過形成性ポリープ(HP)27例,右側HP 18例,左側SSA/P 29例,右側SSA/P 32例を用いた.病理組織学的所見については陰窩の拡張,陰窩の分岐異常,陰窩腺底部の拡張・走行異常(腺底部の所見)の有無について検討した.MUC2,MUC5AC,MUC6,CD10,CDX-2,p53,MLH-1,MSH-2,MSH-6,PMS-2,ANNEXIN A10の発現を免疫組織化学的に検索した.分子解析はKRAS,BRAF変異解析とDNAメチル化解析を行った(高,中等度,低).病理組織学的所見ではSSA/Pで腺底部の所見が右側で有意に多く,各因子の組み合わせパターンでは左側で陰窩の拡張と分岐異常のパターンが多く,右側では3因子すべてのパターンが多かった.MUC6およびANNEXIN A10の発現は右側のSSA/Pで有意に多くみられた.BRAFはSSA/Pで発生部位による違いはなかったが,メチル化では高メチル化状態が右側SSA/Pで高く,中等度メチル化と低メチル化状態が左側のSSA/Pで多かった.HPは左側でKRAS変異の頻度が高かった以外は左右の差異はなかった.SSA/Pでは発生部位によって組織像,分子異常が異なっている可能性が示唆された.(著者抄録)

Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors

Seiko Kamimae, Eiichiro Yamamoto, Masahiro Kai, Takeshi Niinuma, Hiro-o Yamano, Masanori Nojima, Kennjiro Yoshikawa, Tomoaki Kimura, Ryo Takagi, Eiji Harada, Taku Harada, Reo Maruyama, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura, Tamotsu Sugai, Kohzoh Imai, Hiromu Suzuki

ONCOTARGET ( IMPACT JOURNALS LLC ) 6 ( 30 ) 29975 - 29990 2015.10 [Refereed]

Our aim was to identify DNA methylation changes associated with the growth pattern and invasiveness of colorectal cancers (CRCs). Comparison of the methylation statuses of large (>= 20 mm in diameter along the colonic surface) noninvasive tumors (NTs) and small (<20 mm in diameter along the colonic surface) invasive tumors (ITs) using CpG island microarray analysis showed neurotensin receptor 1 (NTSR1) to be hypermethylated in large NTs. Quantitative bisulfite pyrosequencing revealed that NTSR1 is frequently methylated in colorectal tumors, with large NTs exhibiting the highest methylation levels. The higher NTSR1 methylation levels were associated with better prognoses. By contrast, NTSR1 copy number gains were most frequent among small ITs. Methylation of NTSR1 was associated with the gene's silencing in CRC cell lines, whereas ectopic expression of NTSR1 promoted proliferation and invasion by CRC cells. Analysis of primary tumors composed of adenomatous and malignant portions revealed that NTSR1 is frequently methylated in the adenomatous portion, while methylation levels are generally lower in the cancerous portions. These results suggest that NTSR1 methylation is associated with lateral and noninvasive growth of colorectal tumors, while low levels of methylation may contribute to the malignant potential through activation of NTSR1. Our data also indicate that NTSR1 methylation may be a prognostic biomarker in CRC.

大腸癌における腫瘍血管内皮特異的遺伝子の新規同定

萬顕, 山本英一郎, 丸山玲緒, 津矢田明泰, 甲斐正広, 新沼猛, 檜森亮吾, 廣橋良彦, 西舘敏彦, 古畑智久, 平田公一, 菅井有, 鈴木拓

日本癌学会総会記事 ( 日本癌学会 ) 74回 E - 1169 2015.10

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

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

日本癌学会総会記事 ( (一社)日本癌学会 ) 74回 P - 3300 2015.10

Analysis of the molecular features of rectal carcinoid tumors to identify new biomarkers that predict biological malignancy

Kei Mitsuhashi, Itaru Yamamoto, Hiroyoshi Kurihara, Shinichi Kanno, Miki Ito, Hisayoshi Igarashi, Keisuke Ishigami, Yasutaka Sukawa, Mami Tachibana, Hiroaki Takahashi, Takashi Tokino, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Yasuhisa Shinomura, Hiroyuki Yamamoto, Katsuhiko Nosho

ONCOTARGET ( IMPACT JOURNALS LLC ) 6 ( 26 ) 22114 - 22125 2015.09 [Refereed]

Although gastrointestinal carcinoid tumors are relatively rare in the digestive tract, a quarter of them are present in the rectum. In the absence of specific tumor biomarkers, lymphatic or vascular invasion is generally used to predict the risk of lymph node metastasis. We, therefore, examined the genetic and epigenetic alterations potentially associated with lymphovascular invasion among 56 patients with rectal carcinoid tumors. We also conducted a microRNA (miRNA) array analysis. Our analysis failed to detect mutations in BRAF, KRAS, NRAS, or PIK3CA or any microsatellite instability (MSI); however, we did observe CpG island methylator phenotype (CIMP) positivity in 13% (7/56) of the carcinoid tumors. The CIMP-positive status was significantly correlated with lymphovascular invasion (P = 0.036). The array analysis revealed that microRNA-885 (miR-885)-5p was the most up-regulated miRNA in the carcinoid tumors with lymphovascular invasion compared with that in those without invasion. In addition, high miR-885-5p expression was independently associated with lymphovascular invasion (P = 0.0002). In conclusion, our findings suggest that miR-885-5p and CIMP status may be useful biomarkers for predicting biological malignancy in patients with rectal carcinoid tumors.

Low-Frequency IL23R Coding Variant Associated with Crohn's Disease Susceptibility in Japanese Subjects Identified by Personal Genomics Analysis

Kei Onodera, Yoshiaki Arimura, Hiroyuki Isshiki, Kentaro Kawakami, Kanna Nagaishi, Kentaro Yamashita, Eiichiro Yamamoto, Takeshi Niinuma, Yasuyoshi Naishiro, Hiromu Suzuki, Kohzoh Imai, Yasuhisa Shinomura

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 10 ( 9 ) e0137801 2015.09 [Refereed]

Background The common disease-common variant hypothesis is insufficient to explain the complexities of Crohn's disease (CD) genetics; therefore, rare variants are expected to be important in the disease. We explored rare variants associated with susceptibility to CD in Japanese individuals by personal genomic analysis. Methods Two-step analyses were performed. The first step was a trio analysis with whole-exome sequence (WES) analysis and the second was a follow-up case-control association study. The WES analysis pipeline comprised Burrows-Wheeler Aligner, Picard, Genome Analysis Toolkit, and SAMTOOLS. Single nucleotide variants (SNVs)/indels were annotated and filtered by using programs implemented in ANNOVAR in combination with identity-by-descent (IBD), subsequently were subjected to the linkage based, and de novo based strategies. Finally, we conducted an association study that included 176 unrelated subjects with CD and 358 healthy control subjects. Results In family members, 234,067-297,523 SNVs/indels were detected and they were educed to 106-146 by annotation based filtering. Fifty-four CD variants common to both individuals of the affected sib pair were identified. The linkage based strategy detected five candidate variants whereas the de novo based strategy identified no variants. Consequently, five candidates were analyzed in the case-control association study. CD showed a significant association with one variant in exon 4 of IL23R, G149R [rs76418789, P = 3.9E-5, odds ratio (OR) 0.21, 95% confidence interval (CI) 0.09-0.47 for the dominant model (AA + AG versus GG), and P = 7.3E-5, OR 0.21, 95% CI 0.10-0.48 for AG versus GG, and P = 7.2E-5, OR 0.23, 95% CI 0.10-0.50 for the allele model]. Conclusions The present study, using personal genomics analysis of a small CD pedigree, is the first to show that the low-frequency non-synonymous variant of IL23R, rs76418789, protects against CD development in Japanese subjects.

Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway

Miki Ito, Shinichi Kanno, Katsuhiko Nosho, Yasutaka Sukawa, Kei Mitsuhashi, Hiroyoshi Kurihara, Hisayoshi Igarashi, Taiga Takahashi, Mami Tachibana, Hiroaki Takahashi, Shinji Yoshii, Toshinao Takenouchi, Tadashi Hasegawa, Kenji Okita, Koichi Hirata, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura

INTERNATIONAL JOURNAL OF CANCER ( WILEY-BLACKWELL ) 137 ( 6 ) 1258 - 1268 2015.09 [Refereed]

Human gut microbiota is being increasingly recognized as a player in colorectal cancers (CRCs). Evidence suggests that Fusobacterium nucleatum (F. nucleatum) may contribute to disease progression and is associated with CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in CRCs; however, to date, there are no reports about the relationship between F. nucleatum and molecular features in the early stage of colorectal tumorigenesis. Therefore, we investigated the presence of F. nucleatum in premalignant colorectal lesions. In total, 465 premalignant lesions (343 serrated lesions and 122 non-serrated adenomas) and 511 CRCs were studied. We determined the presence of F. nucleatum and analyzed its association with molecular features including CIMP, MSI and microRNA-31 status. F. nucleatum was detected in 24% of hyperplastic polyps, 35% of sessile serrated adenomas (SSAs), 30% of traditional serrated adenomas (TSAs) and 33% of non-serrated adenomas. F. nucleatum was more frequently detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions (p=0.0023). In SSAs, F. nucleatum positivity increased gradually from sigmoid colon to cecum (p=0.042). F. nucleatum positivity was significantly higher in CRCs (56%) than in premalignant lesions of any histological type (p<0.0001). In conclusion, F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP-high lesions. Moreover, F. nucleatum positivity increased according to histological grade, suggesting that it may contribute to the progression of colorectal neoplasia. Our data also indicate that F. nucleatum positivity in SSAs may support the colorectal continuum concept. What's new? Changes in the microbial community in the human gut may contribute to colorectal cancer (CRC). Of particular interest are changes in populations of Fusobacterium nucleatum, which previous work has shown to be abundant in CRC tissues. In this study, F. nucleatum was detected in CRCs, as well as in premalignant lesions with elevated CpG island methylator phenotype status. In sessile serrated adenomas, F. nucleatum increased steadily from the sigmoid colon to the cecum, supporting the existence of a colorectal continuum. F. nucleatum may become increasingly abundant with histological grade and may influence CRC progression.

Comparative analysis of methods to determine DNA methylation levels of a tumor-related microRNA gene

Yuki Konishi, Hiroshi Hayashi, Hiromu Suzuki, Eiichiro Yamamoto, Hajime Sugisaki, Hiroko Higashimoto

ANALYTICAL BIOCHEMISTRY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 484 66 - 71 2015.09 [Refereed]

Quantifying levels of DNA methylation in tumors is a useful approach for the identification of potential tumor suppressors and to find biomarkers that can be used as prognostic or therapeutic indicators. In the current study, we compared three methods commonly used for quantifying DNA methylation bisulfite pyrosequencing, quantitative methylation-specific PCR (Q-MSP), and MethyLight-by focusing on the CpG island of the gene encoding the microRNA-34b and microRNA-34c (miR-34b/c); aberrant regulation of this miR is associated with various human malignancies, including gastric cancer. Standard curve analysis using control DNA samples demonstrated the highest quantitative accuracy in Q-MSP analysis. We also carried out methylation analysis using gastric mucosa specimens obtained from gastric cancer patients. We found a high correlation between methylation levels determined by Q-MSP and those determined by MethyLight (R-2 = 0.952), whereas the results of bisulfite pyrosequencing and the other two methods were less well correlated (R-2 = 0.864 and R-2 = 0.804 for Q-MSP and MethyLight, respectively). This may reflect possible PCR bias in the pyrosequencing technique, which we show can be corrected for by applying a cubic approximate equation to the original data. Thus, although results obtained by the different DNA methylation analysis techniques are largely comparable, an appropriate correction may be necessary for stringent comparison. (C) 2015 Elsevier Inc. All rights reserved.

Contextual niche signals towards colorectal tumor progression by mesenchymal stem cell in the mouse xenograft model

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

JOURNAL OF GASTROENTEROLOGY ( SPRINGER JAPAN KK ) 50 ( 9 ) 962 - 974 2015.09 [Refereed]

The role of mesenchymal stem/stromal cells (MSCs) in tumorigenesis remains controversial. This study aimed to determine whether heterotypic interactions between MSCs and colon cancer cells can supply contextual signals towards tumor progression. Xenografts consisting of co-implanted human colorectal cancer cells with rat MSCs in immunodeficient mice were evaluated by tumor progression, angiogenic profiles, and MSC fate. Furthermore, we investigated how MSCs function as a cancer cell niche by co-culture experiments in vitro. Tumor growth progressed in two ways, either independent of or dependent on MSCs. Such cell line-specific dependency could not be explained by host immune competency. COLO 320 xenograft angiogenesis was MSC-dependent, but less dependent on vascular endothelial growth factor (VEGF), whereas HT-29 angiogenesis was not MSC-dependent, but was VEGF-dependent. MSCs and COLO 320 cells established a functional positive feedback loop that triggered formation of a cancer cell niche, leading to AKT activation. Subsequently, MSCs differentiated into pericytes that enhanced angiogenesis as a perivascular niche. In contrast, the MSC niche conferred an anti-proliferative property to HT-29 cells, through mesenchymal-epithelial transition resulting in p38 activation. In conclusion, MSCs demonstrate pleiotropic capabilities as a cancer cell or perivascular niche to modulate colorectal cancer cell fate in a cell line-dependent manner in a xenogeneic context.

Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer

Ichimura Norihisa, Shinjo Keiko, Ohka Fumiharu, Katsushima Keisuke, Hatanaka Akira, Tojo Masayuki, Shimizu Yasuhiro, Yamamoto Eiichiro, Suzuki Hiromu, Kondo Yutaka

CANCER RESEARCH 75 2015.08 [Refereed]

Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer

Norihisa Ichimura, Keiko Shinjo, Byonggu An, Yasuhiro Shimizu, Kenji Yamao, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Masayuki Tojo, Eiichiro Yamamoto, Hiromu Suzuki, Minoru Ueda, Yutaka Kondo

CANCER PREVENTION RESEARCH ( AMER ASSOC CANCER RESEARCH ) 8 ( 8 ) 702 - 711 2015.08 [Refereed]

Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMPP) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. (C) 2015 AACR.

Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer

Hisayoshi Igarashi, Hiroyoshi Kurihara, Kei Mitsuhashi, Miki Ito, Hiroyuki Okuda, Shinichi Kanno, Takafumi Naito, Shinji Yoshii, Hiroaki Takahashi, Takaya Kusumi, Tadashi Hasegawa, Yasutaka Sukawa, Yasushi Adachi, Kenji Okita, Koichi Hirata, Yu Imamura, Yoshifumi Baba, Kohzoh Imai, Hiromu Suzuki, Hiroyuki Yamamoto, Katsuhiko Nosho, Yasuhisa Shinomura

ANNALS OF SURGICAL ONCOLOGY ( SPRINGER ) 22 ( 8 ) 2640 - 2648 2015.08 [Refereed]

Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer (CRC). We recently reported that microRNA-31 (miR-31)-5p may regulate BRAF activation and play a role in the signaling pathway downstream of EGFR in CRC. Therefore, we hypothesized that miR-31-5p can be a useful biomarker for anti-EGFR therapy in CRC. We evaluated miR-31-5p expression and gene mutations [KRAS (codon 61 or 146), NRAS (codon 12, 13, or 61), and BRAF (V600E)] in the EGFR downstream pathway in 102 CRC patients harboring KRAS (codon 12 or 13) wild-type who were treated with anti-EGFR therapeutics. Progression-free survival (PFS) and overall survival (OS) were evaluated. KRAS (codon 61 or 146), NRAS, and BRAF mutations were detected in 6.9, 6.9, and 5.9 % patients, respectively. Compared with CRCs with at least one mutation (n = 20), significantly better PFS (P = 0.0003) but insignificantly better OS were observed in CRCs harboring all wild-type genes (KRAS, NRAS, and BRAF). High miR-31-5p expression was identified in 11 % (n = 11) patients and was significantly associated with shorter PFS (P = 0.003). In CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS (P = 0.027). High miR-31-5p expression was associated with shorter PFS in patients with CRC treated with anti-EGFR therapeutics. Moreover, in CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS, suggesting that it may be a useful and additional prognostic biomarker for anti-EGFR therapy.

A Screen for Epigenetically Silenced microRNA Genes in Gastrointestinal Stromal Tumors

Mai Isosaka, Takeshi Niinuma, Masanori Nojima, Masahiro Kai, Eiichiro Yamamoto, Reo Maruyama, Takayuki Nobuoka, Toshirou Nishida, Tatsuo Kanda, Takahiro Taguchi, Tadashi Hasegawa, Takashi Tokino, Koichi Hirata, Hiromu Suzuki, Yasuhisa Shinomura

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 10 ( 7 ) e0133754 2015.07 [Refereed]

Background Dysregulation of microRNA (miRNA) has been implicated in gastrointestinal stromal tumors (GISTs) but the mechanism is not fully understood. In this study, we aimed to explore the involvement of epigenetic alteration of miRNA genes in GISTs. Methods GIST-T1 cells were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which miRNA expression profiles were analyzed using TaqMan miRNA arrays. DNA methylation was then analyzed using bisulfite pyrosequencing. The functions of miRNAs were examined using MTT assays, wound-healing assays, Boyden chamber assays and Matrigel invasion assays. Gene expression microarrays were analyzed to assess effect of ectopic miRNA expression in GIST-T1 cells. Results Of the 754 miRNAs analyzed, 61 were significantly upregulated in GIST-T1 cells treated with 5-aza-dC plus PBA. Among those, 21 miRNA genes were associated with an upstream CpG island (CGI), and the CGIs of miR-34a and miR-335 were frequently methylated in GIST-T1 cells and primary GIST specimens. Transfection of miR-34a or miR-335 mimic molecules into GIST-T1 cells suppressed cell proliferation, and miR-34a also inhibited migration and invasion by GIST-T1 cells. Moreover, miR-34a downregulated a number of predicted target genes, including PDGFRA. RNA interference-mediated knockdown of PDGFRA in GIST-T1 cells suppressed cell proliferation, suggesting the tumor suppressive effect of miR-34a is mediated, at least in part, through targeting PDGFRA. Conclusions Our results suggest that miR-34a and miR-335 are candidate tumor suppressive miRNAs in GISTs, and that they are frequent targets of epigenetic silencing in GISTs.

　 PREV - NEXT 　

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

To the head of this page.▲