Papers - SUZUKI Hiromu

The continuum of transformation of TSA to low-grade neoplasia and cancer with BRAF mutation - A case with molecular analysis.

Hironori Aoki, Yasushi Adachi, Eiichiro Yamamoto, Yukinari Yoshida, Yoshifumi Ishii, Hiro-O Yamano, Hiromu Suzuki, Takao Endo

Pathology international   71 ( 5 ) 368 - 370  2021.05  [International journal]

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Lynch症候群を背景とした多発微小大腸癌症例

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

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 )  74 ( 5 ) 332 - 332  2021.05

Lynch症候群を背景とした多発微小大腸癌症例

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

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 )  74 ( 5 ) 332 - 332  2021.05

A genome-wide study of the relationship between chromosomal abnormalities and gene expression in colorectal tumors.

Tamotsu Sugai, Mitsumasa Osakabe, Ryo Sugimoto, Makoto Eizuka, Yoshihito Tanaka, Naoki Yanagawa, Koki Otsuka, Akira Sasaki, Takayuki Matsumoto, Hiromu Suzuki

Genes, chromosomes & cancer   60 ( 4 ) 250 - 262  2021.04  [International journal]

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The role of somatic copy number alterations (SCNAs) that occur in colorectal tumors is poorly understood. SCNAs are correlated with corresponding gene expression changes that may contribute to neoplastic progression. Thus, we examined SCNAs and the expression of messenger RNAs (mRNAs) located at corresponding loci in colorectal neoplasia, a progression model of human neoplasm. We used 42 colorectal neoplastic samples, including adenomas, intramucosal cancers (IMC) and invasive colorectal cancers (CRC) that were microsatellite stable (MSS) using a genome-wide SNP array and gene expression array (first cohort). In addition, validation analyses were examined (37 colorectal neoplasias). None of the mRNAs with a corresponding SCNA was found in the adenomas. However, three mRNAs, including ARFGEF2 at 20q13.13, N4BP2L2 at 13q13.1 and OLFM4 at 13q14.3 with a copy number (CN) gain at the corresponding locus were upregulated in IMCs of the first cohort. Moreover, upregulated expression of ARFGEF2 and OLFM4 was upregulated in the validation analysis. Finally, 28 mRNAs with gains of corresponding loci were pooled in invasive CRC of the first cohort. The mRNAs, including ACSS2 (20q11.22), DDX27 (20q13.13), MAPRE1 (20q11.21), OSBPL2 (20q11.22) and PHF20 (20q11.22-q11.23) with CN gains of the corresponding loci were identified in 28 mRNAs. Four of these mRNAs (DDX27, MAPRE1, OSBPL2 and PHF20) were upregulated in the invasive CRC in the validation analysis. We conclude that specific 13q and 22q CN gains with gene expression changes in the corresponding loci may play an important role in IMC cells' progression into invasive CRC.

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Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.

Kazuya Ishiguro, Hiroshi Kitajima, Takeshi Niinuma, Reo Maruyama, Naotaka Nishiyama, Hitoshi Ohtani, Gota Sudo, Mutsumi Toyota, Hajime Sasaki, Eiichiro Yamamoto, Masahiro Kai, Hiroshi Nakase, Hiromu Suzuki

Cell death discovery   7 ( 1 ) 7 - 7  2021.01  [International journal]

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Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.

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Genome-wide analysis of microRNA to evaluate prognostic markers in isolated cancer glands and surrounding stroma in high-grade serous ovarian carcinoma.

Chie Sato, Mitsumasa Osakabe, Takayuki Nagasawa, Hiromu Suzuki, Hiroaki Itamochi, Tsukasa Baba, Tamotsu Sugai

Oncology letters   20 ( 6 ) 338 - 338  2020.12  [International journal]

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The molecular mechanisms responsible for the progression of ovarian cancer remain incompletely understood. By targeting multiple cancer-related genes, microRNAs (miRNAs) have been identified as key regulators of cancer development and progression. In addition, the microenvironment, which constitutes cancer glands and the surrounding stromal tissue at the invasive front, has an important role in cancer progression. Using array-based analysis of 14 cases (cohort 1), the aim of the present study was to evaluate global miRNA expression in cancerous glands and surrounding stromal tissues (isolated using a crypt isolation method), in order to identify potential prognostic markers of high-grade serous carcinoma (HGSC). Reverse transcription-quantitative PCR was also used to verify the results in cohort 1 (14 cases) and in 16 additional HGSC cases (cohort 2; verification cohort). Firstly, miRNA expression levels were compared between HGSC and normal samples among both the isolated cancer gland and stromal tissue samples. Secondly, miRNA expression was compared between HGSC cases with recurrence and those without recurrence among the isolated cancer gland and stromal tissue samples. The results revealed six and seven miRNAs identified in both of the aforementioned comparisons in isolated cancer glands and surrounding stromal tissue, respectively. Furthermore, downregulation of miRNA-214-3p in isolated cancer glands and downregulation of miRNA-320c in the corresponding stromal tissue were associated with a decrease in disease-free survival (without recurrence) in cohort 2. These findings indicated that specific miRNAs expressed in cancer cells and surrounding stromal cells of HGSC may be potential biomarkers predicting patient prognosis.

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The clinicopathological and molecular features of sporadic gastric foveolar type neoplasia.

Tamotsu Sugai, Noriyuki Uesugi, Wataru Habano, Ryo Sugimoto, Makoto Eizuka, Yasuko Fujita, Mitsumasa Osakabe, Yosuke Toya, Hiromu Suzuki, Takayuki Matsumoto

Virchows Archiv : an international journal of pathology   477 ( 6 ) 835 - 844  2020.12  [International journal]

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Gastric intraepithelial foveolar type neoplasia (IEFN) is not well defined. In addition, atrophic mucosa (AM) is an important issue to consider when evaluating gastric tumorigenesis. Here, we assessed the clinicopathological characteristics and molecular alterations contributing to the development of IEFN compared with intestinal type neoplasia. We examined the clinicopathological and molecular features of 42 cases of IEFN with low-grade dysplasia (LGD) and those of 77 cases of intraepithelial intestinal type neoplasia (IEIN) with LGD. The clinicopathological and molecular features examined included the AM status, mucin phenotype expression, CDX2 expression, p53 overexpression, β-catenin intranuclear accumulation, microsatellite instability (MSI), DNA methylation status (low methylation epigenotype [LME], intermediate ME, or high ME), allelic imbalances (AIs), and APC promoter 1B mutations. There were no differences in the frequencies of AM and rates of CDX2 expression between IEFN and IEIN cases. Although no differences in the frequencies of p53 overexpression and MSI were observed between the two histological types, intranuclear expression of β-catenin was significantly higher in IEIN than in IEFN. In addition, although the rate of LME was significantly higher in IEFN cases than in IEIN cases, IEFN was characterized by AIs at multiple foci. Finally, mutation of the APC promoter 1B, which is a characteristic of gastric adenocarcinoma and proximal polyposis of the stomach (potentially resembling IEFN), was detected in only one IEFN case. These findings suggested that IEFN may be an independent entity in terms of molecular alterations including the presence of multiple AIs and LME.

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【大腸鋸歯状病変の新展開】分類不能鋸歯状病変を由来としたTraditional serrated adenomaの癌化症例

山川 司, 吉井 新二, 市原 真, 大和田 紗恵, 柴田 泰洋, 風間 友江, 平山 大輔, 久保 俊之, 能正 勝彦, 須藤 豪太, 山本 英一郎, 鈴木 拓, 山野 泰穂, 仲瀬 裕志

胃と腸 ( (株)医学書院 )  55 ( 13 ) 1631 - 1638  2020.12

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＜文献概要＞患者は40歳代,女性.血便を主訴に近医を受診し,下部消化管内視鏡検査にて上部直腸(Ra)に径約35mmのLST-GMを認めた.本病変は辺縁に平坦部分を伴い複数の分葉構造を呈し,拡大所見では平坦部分は鋸歯状構造を伴ったII型様pitで構成されていたが,既存の分類には合致しない鋸歯状病変と考えられた.病変の大部分を占める中心の隆起部ではIV型pitを主体としcytological dysplasiaを疑った.病理組織像では平坦部の表層部分にわずかに鋸歯状構造は認めるが,深部はうねった管状腺管で腺腫様であり,免疫染色Ki-67では陽性細胞が散在し腺腫や既存の鋸歯状病変にも当てはまらない組織像であった.一方,隆起部では鋸歯状変化を呈するTSA様の領域と,絨毛状の形態をとりtubulovillous adenomaと考えられる領域が混在していた.また,隆起部の粘膜深部に細胞異型,構造異型が強く,腺管が密に増殖した領域があり,同部位でp53,Ki-67がびまん性の陽性を示しtub1相当の腺癌(Tis)と診断した.遺伝子解析では平坦部,隆起部いずれもKRAS変異陽性(G13D)で一連の病変と考えられた.本症例は内視鏡所見や免疫染色,遺伝子解析結果から既存の分類に当てはまらない鋸歯状病変を基盤として発育進展した病変と考え,ここに報告する.

Sigmoid colon tumor with G-nas mutation presenting unique morphology.

Gota Sudo, Hironori Aoki, Yuko Omori, Hiromu Suzuki, Hiroshi Nakase

Gastrointestinal endoscopy   92 ( 5 ) 1133 - 1135  2020.11  [Refereed]  [International journal]

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AEBP1の発現上昇は大腸がんの腫瘍血管新生を促進する

山本 英一郎, 萬 顕, 新沼 猛, 北嶋 洋志, 甲斐 正広, 鈴木 拓

電気泳動 ( 日本電気泳動学会 )  64 ( Suppl. ) s38 - s38  2020.11

Prolonged oxidative stress and delayed tissue repair exacerbate acetaminophen-induced liver injury in aged mice.

Naoki Tanimizu, Norihisa Ichinohe, Hiromu Suzuki, Toshihiro Mitaka

Aging   12 ( 19 ) 18907 - 18927  2020.10  [International journal]

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The liver gradually loses its regenerative capabilities with aging. However, it remains unknown whether aging affects drug-induced liver injury. Here, we used acetaminophen induced acute liver injury model to compare tissue injury and regeneration of aged mice (>80 weeks old) with young ones (8-10 weeks old). The mortality of aged mice after acetaminophen injury was higher than that of young mice. Transient increase of serum GOT and decrease of reduced glutathione (GSH) were not returned to original levels in aged mice even at 48 hours. In addition, Foxm1b and its targets Ccnd1 and Cdk1 were upregulated in young but not in aged mice after 48 hours. Moreover, an apoptosis-related gene, Cidea, was upregulated specifically in aged livers, which was consistent with increased number of TUNEL+ hepatocytes. Unexpectedly, damaged hepatocytes were retained in aged liver tissue, which may be caused by impaired recruitment of macrophages to the damaged area, without increases in Ccl2 after acetaminophen injury. Collectively, prolonged oxidative stress due to delayed recovery of GSH and the retention of damaged hepatocytes may suppress tissue repair and hepatocyte proliferation, resulting in exacerbation of acetaminophen injury in aged mice. Thus, aging is a risk factor conferring susceptibility against drug-induced liver injury.

DOI PubMed

分類不能鋸歯状病変を伴ったtraditional serrated adenoma癌化症例

山川 司, 吉井 新二, 市原 真, 秋田 浩太朗, 大和田 紗恵, 横山 佳浩, 柴田 泰洋, 風間 友江, 赤保内 正和, 久保 俊之, 仲地 耕平, 能正 勝彦, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 山野 泰穂, 仲瀬 裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 )  62 ( Suppl.2 ) 2150 - 2150  2020.10

分類不能鋸歯状病変を伴ったtraditional serrated adenoma癌化症例

山川 司, 吉井 新二, 市原 真, 秋田 浩太朗, 大和田 紗恵, 横山 佳浩, 柴田 泰洋, 風間 友江, 赤保内 正和, 久保 俊之, 仲地 耕平, 能正 勝彦, 山下 健太郎, 須藤 豪太, 山本 英一郎, 鈴木 拓, 山野 泰穂, 仲瀬 裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 )  62 ( Suppl.2 ) 2150 - 2150  2020.10

頭頸部扁平上皮がんの微小環境におけるAEBP1の解析

萬 顕, 関口 翔平, 山本 英一郎, 新沼 猛, 高澤 啓, 須藤 豪太, 畠中 柚衣, 北嶋 洋志, 甲斐 正広, 小山内 誠, 宮崎 晃亘, 高野 賢一, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  79回   PJ14 - 6  2020.10

AEBP1の発現上昇は大腸がんの腫瘍血管新生を促進する

山本 英一郎, 萬 顕, 新沼 猛, 北嶋 洋志, 須藤 豪太, 甲斐 正広, 高野 賢一, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  79回   OJ14 - 5  2020.10

早期大腸がん浸潤先進部の分子解析

須藤 豪太, 山本 英一郎, 青木 敬則, 高澤 啓, 新沼 猛, 久保 俊之, 萬 顕, 北嶋 洋志, 甲斐 正広, 小山内 誠, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  79回   PJ14 - 8  2020.10

肝芽腫におけるDNAメチル化解析に基づく予後予測モデルの確立

近藤 享史, 本多 昌平, 鈴木 拓, 荒 桃子, 北河 徳彦, 田中 祐吉, 田中 水緒, 新開 真人, 檜山 英三, 武冨 紹信

日本小児血液・がん学会雑誌 ( (一社)日本小児血液・がん学会 )  57 ( 4 ) 255 - 255  2020.10

非乳頭十二指腸腺腫、粘膜内癌におけるゲノム・エピゲノムの統合解析

澤田 武, 佐々木 泰史, 太田 亮介, 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, 鈴木 拓, 時野 隆至, 源 利成

日本癌学会総会記事 ( (一社)日本癌学会 )  79回   OJ14 - 5  2020.10

新規癌抑制遺伝子SALL3はトリプルネガティブ乳癌の薬剤抵抗性に関与する

松下 洋輔, 小松 正人, 清谷 一馬, 吉丸 哲郎, 新沼 猛, 鈴木 拓, 本田 純子, 井本 逸勢, 丹黒 章, 三好 康雄, 笹 三徳, 片桐 豊雅

日本癌学会総会記事 ( (一社)日本癌学会 )  79回   OJ14 - 7  2020.10

Dysregulation of microRNA expression during the progression of colorectal tumors.

Makoto Eizuka, Mitsumasa Osakabe, Ayaka Sato, Yasuko Fujita, Yoshihito Tanaka, Koki Otsuka, Akira Sasaki, Takayuki Matsumoto, Hiromu Suzuki, Tamotsu Sugai

Pathology international   70 ( 9 ) 633 - 643  2020.09  [International journal]

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MicroRNAs (miRNAs) are potential biomarkers of neoplastic lesions, but additional information on dysregulated miRNA expression during progression of the adenoma-adenocarcinoma sequence may be helpful to identify the role of miRNAs in this sequence. We examined the expression levels of 13 miRNAs (hsa-miRNA-19a-3p, hsa-miRNA-21-5p, hsa-miRNA-27a-3p, hsa-miRNA-27b-3p, hsa-miRNA-31-5p, hsa-miRNA-34b-3p, hsa-miRNA-125b-5p, hsa-miRNA-143-3p, miRNA-191-5p, hsa-miRNA-193b-3p, hsa-miRNA-195-5p, hsa-miRNA-206 and hsa-let-7a-5p) that are closely associated with colorectal carcinogenesis in 40 conventional adenomas (tubular and tubulovillous adenomas), 20 intramucosal carcinomas (IMCs) and 60 invasive colorectal cancers (iCRCs) using reverse-transcription polymerase chain reaction. These 120 tumors were divided into two cohorts, that is, cohort 1 (60 cases) and cohort 2 (for validation; 60 cases). We analyzed the expression levels of these miRNAs in the first step (adenoma→IMC) and second step IMC→iCRC) of the adenoma-carcinoma sequence in both cohorts. Although no significant differences in the expression of any of the 13 miRNAs were found between adenomas and IMCs consistently in both cohorts, the expression levels of hsa-miRNA-125b-5p, hsa-miRNA-143-3p, and hsa-miRNA-206 were significantly upregulated in iCRC in both cohorts compared with those in IMC. The current results suggest that certain miRNAs, including hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206, are candidate markers that play critical roles in the progression of IMC to iCRC.

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