Papers - SUZUKI Hiromu

Traditional serrated adenoma has two distinct genetic pathways for molecular tumorigenesis with potential neoplastic progression.

Yoshihito Tanaka, Makoto Eizuka, Noriyuki Uesugi, Keisuke Kawasaki, Hiroo Yamano, Hiromu Suzuki, Takayuki Matsumoto, Tamotsu Sugai

Journal of gastroenterology   55 ( 9 ) 846 - 857  2020.09  [Domestic journal]

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BACKGROUND: Recent studies have shown that traditional serrated adenoma (TSA) can be classified into BRAF and KRAS subtypes. Here, we examined the clinicopathological and molecular findings of 73 TSAs. MATERIALS AND METHODS: TSAs were subclassified into BRAF type (46 cases, type A) and KRAS type (27 cases, type B) and divided into polyp head (TSA component) and base (precursor component [PC]) to identify pathological and molecular differences between the two components. BRAF and KRAS mutations, microsatellite instability (MSI), and DNA methylation status of the TSA component and PC were analyzed. In addition, immunohistochemical expressions of annexin A10, MUC2, MUC5AC, MUC6, and CD10 were also examined. Finally, we compared endoscopic findings with histological features. RESULTS: We classified type As into 31 type A1s with mutation of the corresponding PC (42.5%) and 15 type A2s without mutation of the PC (20.5%). None of the corresponding PCs without KRAS mutation were observed in type Bs. MSI was not detected in the TSAs examined. There were significant differences in the frequency of annexin A10 and MUC5AC expression between the three subtypes. Furthermore, we compared the TSA component with the corresponding PC to identify the progression mechanism between the two components. Methylation status played an important role in the progression of type A1 from the corresponding PC, unlike type A2 and type B. Finally, specific endoscopic findings were well correlated with distinct histological findings. CONCLUSION: TSAs were heterogeneous tumors with two or three pathways to neoplastic progression.

DOI PubMed

Aggressive variant of splenic marginal zone lymphoma characterized using a cancer panel test and treated with rituximab-containing chemotherapy: A case report.

Kazuya Ishiguro, Yasushi Sasaki, Yoshitake Takagi, Takeshi Niinuma, Hiromu Suzuki, Takashi Tokino, Toshiaki Hayashi, Tohru Takahashi, Tetsuyuki Igarashi, Yoshihiro Matsuno

Medicine   99 ( 35 ) e21938  2020.08  [International journal]

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RATIONALE: Aggressive variant of splenic marginal zone lymphoma (AV-SMZL) is a very rare disease that is often associated with TP53 mutations and has a poor prognosis. On the other hand, recent advances in genome sequencing techniques enable us to understand the molecular characteristics of rare cancers such as AV-SMZL. Here we present a case of AV-SMZL analyzed using a genetic test. PATIENT CONCERNS: A 66-year-old woman was admitted with splenomegaly and lymphocytosis. Computed tomography revealed marked splenomegaly without lymphadenopathy in any other areas. The serum soluble interleukin-2 receptor (sIL-2R) level was significantly elevated. Peripheral and bone marrow blood tests showed an increase in abnormal lymphocytes. DIAGNOSIS: A splenectomy revealed an SMZL pattern with increased numbers of large cells and mitotic cells and a high Ki-67 positivity rate, which led to a diagnosis of AV-SMZL. Although TP53 mutation was not detected, mutations in NOTCH2, NCOA4, PTEN, EPHA3, and KMT2D were identified. Among these, the mutations in NCOA4, PTEN, and EPHA3 were novel pathogenic mutations in SMZL, which suggests they may be related to the aggressiveness and persistence of the disease. INTERVENTIONS: The patient was administered a rituximab-containing regimen and rituximab-maintenance therapy. OUTCOMES: The patient continues to exhibit a complete response. LESSONS: This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.

DOI PubMed

SSA/P由来が示唆された横行結腸SM癌の一例

久保 俊之, 山野 泰穂, 中村 友哉, 柴田 泰洋, 山川 司, 風間 友江, 赤保内 正和, 吉井 新二, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 永塚 真, 菅井 有, 杉田 真太朗, 長谷川 匡, 遠藤 高夫, 仲瀬 裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 )  62 ( Suppl.1 ) 1327 - 1327  2020.08

横行結腸に発生したcytological dysplasiaを伴う分類困難な鋸歯状病変の1例

秋田 浩太朗, 山野 泰穂, 柴田 泰洋, 久保 俊之, 吉井 新二, 横山 佳浩, 風間 友江, 三橋 慧, 能正 勝彦, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 寺井 琴美, 辻脇 光洋, 長谷川 匡, 永塚 真, 菅井 有, 仲瀬 裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 )  62 ( Suppl.1 ) 1265 - 1265  2020.08

Superficially serrated adenoma(SuSA)の発がんが観察された微小大腸癌の1例

柴田 泰洋, 山野 泰穂, 久保 俊之, 吉井 新二, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 寺井 琴美, 長谷川 匡, 永塚 真, 菅井 有, 仲瀬 裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 )  62 ( Suppl.1 ) 1265 - 1265  2020.08

Lynch症候群に合併した多発微小大腸癌の1例

柴田 泰洋, 山野 泰穂, 久保 俊之, 吉井 新二, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 寺井 琴美, 長谷川 匡, 永塚 真, 菅井 有, 仲瀬 裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  117 ( 臨増総会 ) A319 - A319  2020.07

新規大腸がん間質関連遺伝子の同定とがん微小環境における機能の解明

須藤 豪太, 山本 英一郎, 三橋 慧, 久保 俊之, 山野 泰穂, 鈴木 拓, 仲瀬 裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  117 ( 臨増総会 ) A318 - A318  2020.07

Lynch症候群に合併した多発微小大腸癌の1例

柴田 泰洋, 山野 泰穂, 久保 俊之, 吉井 新二, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 寺井 琴美, 長谷川 匡, 永塚 真, 菅井 有, 仲瀬 裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  117 ( 臨増総会 ) A319 - A319  2020.07

Upregulation of adipocyte enhancer-binding protein 1 in endothelial cells promotes tumor angiogenesis in colorectal cancer.

Akira Yorozu, Eiichiro Yamamoto, Takeshi Niinuma, Akihiro Tsuyada, Reo Maruyama, Hiroshi Kitajima, Yuto Numata, Masahiro Kai, Gota Sudo, Toshiyuki Kubo, Toshihiko Nishidate, Kenji Okita, Ichiro Takemasa, Hiroshi Nakase, Tamotsu Sugai, Kenichi Takano, Hiromu Suzuki

Cancer science   111 ( 5 ) 1631 - 1644  2020.05  [Refereed]  [International journal]

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Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT-PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.

DOI PubMed

大腸がんにおけるAEBP1の発現上昇は腫瘍血管新生を促進する

鈴木 拓, 萬 顕, 山本 英一郎, 新沼 猛, 北嶋 洋志, 甲斐 正広, 仲瀬 裕志

日本臨床分子医学会学術総会プログラム・抄録集 ( 日本臨床分子医学会 )  57回   63 - 63  2020.04

消化器がん内視鏡診断・治療の最前線 大腸腫瘍性病変に対するTranslational researchの確立を目指した内視鏡診療

赤保内 正和, 吉井 新二, 鈴木 拓, 山野 泰穂, 仲瀬 裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  126回・120回   34 - 34  2020.03

Hypermethylation of CSF3R is a novel cisplatin resistance marker and predictor of response to postoperative chemotherapy in hepatoblastoma.

Sunao Fujiyoshi, Shohei Honda, Masashi Minato, Momoko Ara, Hiromu Suzuki, Eiso Hiyama, Akinobu Taketomi

Hepatology research : the official journal of the Japan Society of Hepatology    2020.01  [Refereed]  [International journal]

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AIM: Most hepatoblastoma patients undergo pre/postoperative cisplatin treatment. Approximately 20% patients are cisplatin resistant, and show poor prognosis and high recurrence rates. However, some cisplatin-sensitive patients show early recurrence. We consider that a small population of cisplatin-resistant cells may remain after preoperative chemotherapy. Previous studies showed a correlation between DNA hypermethylation and hepatoblastoma progression. Here, we examined whether DNA hypermethylation was related to cisplatin resistance and could be a potential indicator for cisplatin as postoperative chemotherapy. METHODS: We extracted DNA from 43 resected hepatoblastoma tumors. Methylation array analyses were performed in 11 samples, including six cisplatin-sensitive and five cisplatin-resistant samples. We also performed cDNA microarray analysis in parental and cisplatin-resistant HuH6 cells. Through comparison of the datasets, we selected the strongest correlated cisplatin-resistant candidate gene. Using bisulfite pyrosequencing, the candidate gene methylation level was assessed in 38 cisplatin-sensitive patients after checking its usefulness as a substitute modality of methylation array. Correlations between the methylation status and clinical data were analyzed. RESULTS: CSF3R was the strongest correlated variable. Bisulfite pyrosequencing analysis also confirmed CSF3R was significantly hypermethylated in cisplatin-resistant patients. Among the 38 cisplatin-sensitive patients, recurrence curves showed that the CSF3R high methylation patients had significantly higher recurrence than CSF3R low methylation patients. The recurrence curve of methylation high patients was similar to that of cisplatin-resistant patients. CONCLUSIONS: Our findings suggested that CSF3R hypermethylation was related to cisplatin resistance in HB patients and could be a predictor of postoperative chemotherapy, and indicate that CSF3R high methylation patients should be treated with non-CDDP regimens.

DOI PubMed

Differential expression of microRNAs in colorectal cancer: Different patterns between isolated cancer gland and stromal cells

Ayaka Sato, Yasuko Fujita, Koki Otsuka, Akira Sasaki, Hiromu Suzuki, Takayuki Matsumoto, Tamotsu Sugai

Pathology International ( Blackwell Publishing )  70 ( 1 ) 21 - 30  2020.01

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Although microRNAs (miRNAs) play an important role in invasive tumor lesions, which involve cancer tissues mixed with stromal tissues, the differences in miRNA expression between cancer and stromal cells remain unclear. We selected 13 miRNAs and examined their differential expression patterns in cancer gland cells and surrounding stromal cells isolated from 24 colorectal cancer (CRC) specimens using a crypt isolation method. Although six miRNAs were upregulated in gland cells, only three were upregulated in the corresponding stromal cells, in the cancer compared with non-cancer specimens. Next, we examined the differences in miRNA expression between isolated cancer gland and stromal cells. Five miRNAs showed statistical differences in their cancer-related differential expression patterns between isolated cancer gland and stromal cells. We then compared these miRNA expression patterns in isolated cancer gland and stromal cells with those in fresh intact tumor tissues, consisting of cancer nests and stromal tissue, obtained from the 24 CRCs. The expression patterns of three miRNAs in the intact cancer tissue samples did not correspond with those in the isolated components. Identification of the expression patterns of miRNAs in both the cancer gland and stromal cell components of the tumor microenvironment greatly contributes to evaluating epigenetic regulation in CRC.

DOI PubMed

Self-Renewal Capability of Hepatocytic Parental Progenitor Cells Derived From Adult Rat Liver Is Maintained Long Term When Cultured on Laminin 111 in Serum-Free Medium.

Junichi Kino, Norihisa Ichinohe, Masayuki Ishii, Hiromu Suzuki, Toru Mizuguchi, Naoki Tanimizu, Toshihiro Mitaka

Hepatology communications   4 ( 1 ) 21 - 37  2020.01  [International journal]

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In this study, we investigated how the ability of hepatocytic parental progenitor cells (HPPCs) to self-renew can be maintained and how laminin (LN) isoforms play an important role in their self-renewal and maturation. Hepatocytes isolated from adult rat livers were cultured on hyaluronic acid to form colonies consisting of CD44+ small hepatocytes, which could be passaged on dishes coated with Matrigel. When second-passage cells were plated on Matrigel, LN111, or LN511, HPPCs appeared on Matrigel and LN111 but not on LN511. We identified two types of cells among the second-passage cells: Small, round cells and large, flat ones were observed on Matrigel, whereas the former and latter ones were specifically attached on LN111 and LN511, respectively. We hypothesized that small and round cells are the origin of HPPC colonies, and the binding to LN111 could be key to maintaining their self-renewal capability. Among the integrins involved in LN binding, integrins α3 and β1 were expressed in colonies on LN111 more than in those on LN511, whereas β4 was more strongly expressed in colonies on LN511. Integrin α3highα6β1high cells could form HPPC colonies on LN111 but not on LN511, whereas integrin α6β1low cells could not on either LN111 or LN511. In addition, neutralizing anti-integrin β1 and anti-LN111 antibodies inhibited the passaged cells' ability to attach and form colonies on LN111 by HPPCs. Matrigel overlay induced second-passage cells growing on LN111 to increase their expression of hepatic functional genes and to form 3-dimensional colonies with bile canalicular networks, whereas such a shift was poorly induced when they were grown onLN511. Conclusion: These results suggest that the self-renewal capability of HPPCs depends on LN111 through integrin β1 signaling.

DOI PubMed

「消化管腫瘍学の最前線-臨床と基礎のブリッジング」-オミックス解析に基づいた消化管腫瘍分子腫瘍発生理論の新展開- 非乳頭十二指腸腫瘍におけるDNAメチル化と遺伝子変異の統合解析

澤田 武, 太田 亮介, 津山 翔, 八尾 隆史, 波佐谷 兼慶, 海崎 泰治, 中西 宏佳, 吉田 尚弘, 辻 重継, 土山 寿志, 湊 宏, 山本 英一郎, 久保田 英嗣, 片岡 洋望, 佐々木 泰史, 源 利成, 鈴木 拓

日本消化管学会雑誌 ( (一社)日本消化管学会 )  4 ( Suppl. ) 136 - 136  2020.01

【エピジェネティクスと疾患】DNAメチル化

新沼 猛, 鈴木 拓

医学のあゆみ ( 医歯薬出版(株) )  272 ( 1 ) 4 - 9  2020.01

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DNAのメチル化は最もよく知られたエピジェネティック修飾のひとつであり、発生、分化から加齢、がんを含む多くの疾患まで広範な生命現象に関連している。DNAメチル化にはメチル基転移酵素であるDNAメチルトランスフェラーゼ(DNMT)ファミリーが関与しており、DNA複製の際の維持メチル化やde novoメチル化を制御している。また、TETファミリー蛋白による能動的なDNA脱メチル化も、DNAメチル化を制御する重要な因子であることが知られている。また、DNAメチル化を介した遺伝子発現制御には、メチル化DNA結合蛋白など種々の分子群が関連している。これらの複数の機構が細胞特異的なDNAメチル化や遺伝子発現を規定している。本稿では、DNAメチル化制御に関連する分子の構築、調節機構について紹介し、さらに発生時におけるDNAメチル化レベルのダイナミックな変化について述べる。(著者抄録)

Significance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum.

Hiroyoshi Nakanishi, Takeshi Sawada, Yasuharu Kaizaki, Ryosuke Ota, Hiromu Suzuki, Eiichiro Yamamoto, Hironori Aoki, Makoto Eizuka, Kenkei Hasatani, Naoki Takahashi, Satoko Inagaki, Masahide Ebi, Hiroyuki Kato, Eiji Kubota, Hiromi Kataoka, Satoru Takahashi, Takashi Tokino, Toshinari Minamoto, Tamotsu Sugai, Yasushi Sasaki

PloS one   15 ( 2 ) e0229262  2020  [Refereed]  [International journal]

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Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear β-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.

DOI PubMed

肝細胞癌におけるBRD4阻害の抗腫瘍効果メカニズムの解析(Analysis of the anti-tumor mechanism of BRD4 inhibition in hepatocellular carcinoma)

佐々木 基, 北嶋 洋志, 新沼 猛, 若杉 英樹, 石黒 一也, 萬 顕, 須藤 豪太, 畠平 知, 阿久津 典之, 山本 英一郎, 甲斐 正広, 佐々木 茂, 仲瀬 裕志, 鈴木 拓

札幌医学雑誌 ( 札幌医科大学 )  88 ( 1-6 ) 21 - 35  2019.12

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BRD4を含むBETファミリー蛋白質はアセチル化ヒストンのリーダー蛋白質であり、転写調節において重要な役割を担っている。BRD4阻害剤は様々な悪性腫瘍において抗腫瘍効果を示す事が報告されている。今回我々は、肝細胞癌におけるBRD4阻害の抗腫瘍効果メカニズムの解明を目的とした。まずBRD4阻害剤JQ1の抗腫瘍効果を9種類の肝癌細胞株を用いて検証した結果、増殖抑制、細胞周期停止、アポトーシスの誘導が認められた。次に我々は、JQ1が遺伝子発現に与える影響をマイクロアレイによって解析した。その結果、JQ1が細胞周期やアポトーシス関連遺伝子に強い影響を与えること、そしてBCAT1、DDR1、GDF15、FANCD2、SENP1、TYRO3など複数の肝細胞癌関連遺伝子の発現を抑制することを見いだした。これらの遺伝子のプロモーター領域へのBRD4結合が確認されたことから、これらは肝細胞癌におけるBRD4の標的遺伝子と考えられた。今回の結果から、BRD4阻害剤は複数の癌関連遺伝子を抑制することで、肝細胞癌に対する抗腫瘍効果を示すと考えられた。(著者抄録)

Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months.

Sadahiro Amemori, Hiro-O Yamano, Yoshihito Tanaka, Kenjiro Yoshikawa, Hiro-O Matsushita, Ryo Takagi, Eiji Harada, Yuko Yoshida, Kazunori Tsuda, Bunichiro Kato, Eri Tamura, Makoto Eizuka, Tamotsu Sugai, Yasushi Adachi, Eiichiro Yamamoto, Hiromu Suzuki, Hiroshi Nakase

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society   32 ( 6 ) 979 - 983  2019.11  [Refereed]  [International journal]

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Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.

DOI PubMed

非乳頭十二指腸腫瘍におけるDNAメチル化解析(Methylation analysis of non-ampullary duodenal precancerous and cancerous lesions)

澤田 武, 太田 亮介, 鈴木 拓, 津山 翔, 八尾 隆史, 中西 宏佳, 山本 英一郎, 久保田 英嗣, 片岡 洋望, 佐々木 泰史, 源 利成

日本癌学会総会記事 ( 日本癌学会 )  78回   P - 2036  2019.09