SUZUKI Hiromu

写真a

Affiliation

School of Medicine, Department of Molecular Biology

Job title

Professor

Degree 【 display / non-display

  • M.D., Ph.D.

Research Experience 【 display / non-display

  • 2012.08
    -
    Now

    Sapporo Medical University   School of Medicine, Department of Molecular Biorogy   教授

    教授

  • 2011.07
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    2012.07

    Sapporo Medical University   School of Medicine, Department of Molecular Biorogy   助教

    助教

  • 2007.04
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    2011.06

    Sapporo Medical University   医学部内科学第一講座   助教

    助教

  • 2004.04
    -
    2007.03

    Sapporo Medical University   School of Medicine, Dept.of Public Health   助手

    助手

  • 2000.05
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    2003.11

    Johns Hopkins University   Oncology Center   Postdoctoral fellow

    Postdoctoral fellow

Professional Memberships 【 display / non-display

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    日本癌学会

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    Japan Society for Molecular Tumor Marker Research

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    日本分子生物学会

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    日本分子腫瘍マーカー研究会

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    American Association for Cancer Reserach

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Research Areas 【 display / non-display

  • Life sciences   Tumor biology  

  • Life sciences   Tumor diagnostics and therapeutics  

Affiliation 【 display / non-display

  • Sapporo Medical University   School of Medicine, Dept. of Molecular Biology   Professor  

 

Research Interests 【 display / non-display

  • 内科

  • エピジェネティクス

Papers 【 display / non-display

  • Downregulation of SMOC1 is associated with progression of colorectal traditional serrated adenomas.

    Hironori Aoki, Akira Takasawa, Eiichiro Yamamoto, Takeshi Niinuma, Hiro-O Yamano, Taku Harada, Toshiyuki Kubo, Akira Yorozu, Hiroshi Kitajima, Kazuya Ishiguro, Masahiro Kai, Akio Katanuma, Toshiya Shinohara, Hiroshi Nakase, Tamotsu Sugai, Makoto Osanai, Hiromu Suzuki

    BMC gastroenterology   24 ( 1 ) 91 - 91  2024.03  [International journal]

     View Summary

    BACKGROUND: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. METHODS: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). RESULTS: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. CONCLUSION: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

    DOI PubMed

  • Physical Properties and Cellular Metabolic Characteristics of 3D Spheroids Are Possible Definitive Indices for the Biological Nature of Cancer-Associated Fibroblasts.

    Nami Nishikiori, Kohichi Takada, Tatsuya Sato, Sho Miyamoto, Megumi Watanabe, Yui Hirakawa, Shohei Sekiguchi, Masato Furuhashi, Akira Yorozu, Kenichi Takano, Akihiro Miyazaki, Hiromu Suzuki, Hiroshi Ohguro

    Cells   12 ( 17 )  2023.08  [International journal]

     View Summary

    The current study's objective was to elucidate some currently unknown biological indicators to evaluate the biological nature of cancer-associated fibroblasts (CAFs). For this purpose, four different CAFs, CAFS1, CAFS2, SCC17F and MO-1000, were established using surgical specimens from oral squamous cell carcinomas (OSCC) with different clinical malignant stages (CAFS1 and CAFS2, T2N0M0, stage II; SCC17F and MO-1000, T4aN2bM0, stage IVA). Fibroblasts unrelated to cancer (non-CAFs) were also prepared and used as controls. Initially, confirmation that these four fibroblasts were indeed CAFs was obtained by their mRNA expression using positive and negative markers for the CAF or fibroblasts. To elucidate possible unknown biological indicators, these fibroblasts were subjected to a cellular metabolic analysis by a Seahorse bioanalyzer, in conjugation with 3D spheroid cultures of the cells and co-cultures with a pancreas ductal carcinoma cell line, MIA PaCa-2. The mitochondrial and glycolytic functions of human orbital fibroblasts (HOF) were nearly identical to those of Graves'-disease-related HOF (GOF). In contrast, the characteristics of the metabolic functions of these four CAFs were different from those of human conjunctival fibroblasts (HconF), a representative non-CAF. It is particularly noteworthy that CAFS1 and CAFS2 showed markedly reduced ratios for the rate of oxygen consumption to the extracellular acidification rate, suggesting that glycolysis was enhanced compared to mitochondrial respiration. Similarly, the physical aspects, their appearance and stiffness, of their 3D spheroids and fibroblasts that were induced effects based on the cellular metabolic functions of MIA PaCa-2 were also different between CAFs and non-CAFs, and their levels for CAFS1 or SCC17F were similar to those for CAFS2 or MO-1000 cells, respectively. The findings reported herein indicate that cellular metabolic functions and the physical characteristics of these types of 3D spheroids may be valuable and useful indicators for estimating potential biological diversity among various CAFs.

    DOI PubMed

  • ACLP Activates Cancer-Associated Fibroblasts and Inhibits CD8+ T-Cell Infiltration in Oral Squamous Cell Carcinoma.

    Shohei Sekiguchi, Akira Yorozu, Fumika Okazaki, Takeshi Niinuma, Akira Takasawa, Eiichiro Yamamoto, Hiroshi Kitajima, Toshiyuki Kubo, Yui Hatanaka, Koyo Nishiyama, Kazuhiro Ogi, Hironari Dehari, Atsushi Kondo, Makoto Kurose, Kazufumi Obata, Akito Kakiuchi, Masahiro Kai, Yoshihiko Hirohashi, Toshihiko Torigoe, Takashi Kojima, Makoto Osanai, Kenichi Takano, Akihiro Miyazaki, Hiromu Suzuki

    Cancers   15 ( 17 )  2023.08  [International journal]

     View Summary

    We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-β1, suggesting cancer-cell-derived TGF-β1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target.

    DOI PubMed

  • TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

    Hiroshi Kitajima, Reo Maruyama, Takeshi Niinuma, Eiichiro Yamamoto, Akira Takasawa, Kumi Takasawa, Kazuya Ishiguro, Akihiro Tsuyada, Ryo Suzuki, Gota Sudo, Toshiyuki Kubo, Kei Mitsuhashi, Masashi Idogawa, Shoichiro Tange, Mutsumi Toyota, Ayano Yoshido, Kohei Kumegawa, Masahiro Kai, Kazuyoshi Yanagihara, Takashi Tokino, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

    Cell Death & Disease ( Springer Science and Business Media LLC )  14 ( 7 )  2023.07

     View Summary

    Abstract Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

    DOI

  • Human Neuralized is a novel tumour suppressor targeting Wnt/β-catenin signalling in colon cancer.

    Joo Mi Yi, Tae-Hong Kang, Yu Kyeong Han, Ha Young Park, Ju Hwan Yang, Jin-Han Bae, Jung-Soo Suh, Tae-Jin Kim, Joong-Gook Kim, Yan-Hong Cui, Hiromu Suzuki, Kohei Kumegawa, Sung Joo Kim, Yi Zhao, In Ja Park, Seung-Mo Hong, Joon-Yong Chung, Su-Jae Lee

    EMBO reports     e56335  2023.06  [International journal]

     View Summary

    While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/β-catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL-mediated oncogenic β-catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic β-catenin, and reducing its cytoplasmic levels in a GSK3β- and β-TrCP-independent manner, indicating that NEURL-β-catenin interactions can lead to a disruption of the canonical Wnt/β-catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/β-catenin signalling.

    DOI PubMed

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Misc 【 display / non-display

  • Analysis of AEBP1 in the microenvironment of head and neck squamous cell carcinoma

    Shohei Sekiguchi, Akira Yorozu, Eiichiro Yamamoto, Takeshi Niinuma, Akira Takasawa, Gota Sudo, Kazushige Koike, Yui Hatanaka, Ayano Yoshido, Hiroshi Kitajima, Masahiro Kai, Makoto Osanai, Kenichi Takano, Akihiro Miyazaki, Hiromu Suzuki

    CANCER SCIENCE ( WILEY )  113   1506 - 1506  2022.02

    Research paper, summary (international conference)  

  • Epigenetic alteration of SALL3 contributes to chemoresistance in triple-negative breast cancer

    Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Takeshi Niinuma, Hiromu Suzuki, Tetsuro Yoshimaru, Atsushi Tajima, Issei Imoto, Junko Honda, Yoichi Furukawa, Yusuke Nakamura, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri

    CANCER SCIENCE ( WILEY )  113   752 - 752  2022.02

    Research paper, summary (international conference)  

  • LOW EXPRESSION OF miRNA-199-5p AND miRNA-374 CAN PREDICT THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B AFTER ADMINISTRATION OF NUCLEOSIDE ANALOG.

    Hideaki Takahashi, Chiaki Okuse, Norie Yamada, Takeshi Niinuma, Masahiro Kai, Hideki Wakasugi, Noriyuki Akutsu, Hiroshi Yotsuyanagi, Michihiro Suzuki, Hiromu Suzuki, Fumio Itoh

    HEPATOLOGY ( WILEY )  74   656A - 657A  2021.10

    Research paper, summary (international conference)  

  • SMOC1の大腸腫瘍診断マーカーとしての臨床的有用性の検討

    青木 敬則, 山本 英一郎, 高澤 啓, 新沼 猛, 山野 泰穂, 萬 顕, 北嶋 洋志, 甲斐 正広, 小山内 誠, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [P14 - 4]  2021.09

  • 頭頸部扁平上皮癌の癌微小環境におけるAEBP1の解析

    萬 顕, 山本 圭佑, 小幡 和史, 大國 毅, 黒瀬 誠, 近藤 敦, 高澤 啓, 小島 隆, 鈴木 拓, 高野 賢一

    日本耳鼻咽喉科学会会報 ( (一社)日本耳鼻咽喉科頭頸部外科学会 )  124 ( 4 ) 690 - 690  2021.04

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Awards 【 display / non-display

  • 田原榮一賞

    2017   日本消化器癌発生学会  

    Winner: 鈴木 拓

  • 北海道医師会賞・北海道知事賞

    2016  

    Winner: 鈴木 拓

  • 北海道科学技術奨励賞

    2014  

    Winner: 鈴木 拓

  • 第19回日本消化器癌発生学会総会最優秀賞

    2008  

    Winner: 鈴木 拓

  • 日本臨床分子医学会学術奨励賞

    2005  

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Research Projects 【 display / non-display

  • DOT1L阻害によるインターフェロン応答の機序解明とがん免疫療法への応用

    基盤研究(B)

    Project Year :

    2022.04
    -
    2025.03
     

    鈴木 拓, 仲瀬 裕志, 新沼 猛, 北嶋 洋志

  • 肝芽腫発生モデルを利用したエピゲノム異常がもたらす抗がん剤耐性機序の解明

    基盤研究(C)

    Project Year :

    2022.04
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    2025.03
     

    本多 昌平, 北河 徳彦, 鈴木 拓, 田中 祐吉

  • ジアシルグリセロールキナーゼが関与するがん進行機構の探索

    基盤研究(C)

    Project Year :

    2022.04
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    2025.03
     

    甲斐 正広, 鈴木 拓

  • がん細胞のインターフェロンシグナルを制御する長鎖noncoding RNAの解析

    基盤研究(C)

    Project Year :

    2021.04
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    2024.03
     

    新沼 猛, 鈴木 拓

     View Summary

    消化器癌におけるDLEU1の機能解析を行うために大腸癌細胞株RKO、HCT116、DLD1、SW480を用いてDLEU1をノックダウンし細胞増殖に与える影響についてCCK-8を用いたcell viability assayを行った。大腸癌についてはいずれの細胞株においてもDLEU1のノックダウンは細胞増殖を抑制した。DLEU1のノックダウンがIFNシグナルに与える影響を調べるためにDLD1、SW480においてIFITM1、IFITM3の発現をRT-qPCRにて解析したところ、口腔扁平上皮癌と異なり、これらのISGsは発現が不変~上昇傾向であった。HCT116においてはDLEU1のノックダウンによりIFITM1は発現低下、IFITM3は発現上昇、RKOにおいてはIFITM1は発現低下が認められた。DLD1、SW480ではIFITM1、IFITM3ともDLEU1のノックダウンにより発現が上昇傾向であった。さらに他の消化器癌においてDLEU1の機能を解析するために食道癌細胞株であるTE5、TE9、TE15を用いてDLEU1をノックダウンし、細胞増殖に与える影響についてcell viability assayを行った。異なるsiRNAを用いて解析したが、食道癌においてはDLEU1のノックダウンにより増殖の亢進、抑制いずれも起こり一定の傾向が認められなかった。ISGsに与える影響についてもRT-qPCRによりIFITM3、IFITM1の発現も解析したが、発現の上昇・低下いずれも認められ一定の傾向を示さなかった。TE-5においてはIFITM1、IFITM3は発現が低下傾向であったが、TE-9においてはIFITM3は発現が上昇、TE-15はIFITM1の発現が低下傾向であった。

  • 胃がん関連長鎖non-coding RNAによるストレス顆粒と発がん機構の解析

    基盤研究(C)

    Project Year :

    2021.04
    -
    2024.03
     

    北嶋 洋志, 鈴木 拓

     View Summary

    申請者らは先行実験により慢性胃炎および胃がんで発現が亢進する長鎖non-coding RNA (lncRNA) TM4SF1AS1がストレス顆粒の形成促進とアポトーシスの抑制に関与することを明らかにしたが、その詳細なメカニズムは不明である。本研究はその分子機構を明らかにすることを目的としている。 TM4SF1AS1の詳細な細胞内の局在情報を得るために、MS2タグを付加したTM4SF1AS1のTet-on遺伝子発現誘導系胃がん細胞株を樹立し、免疫蛍光染色を行った。ストレス顆粒マーカーであるTIA-1、G3BP1やG3BP2と共にTM4SF1AS1がその過剰発現によって形成された顆粒様構造に局在することが示された。 また、TM4SF1AS1との相互作用が見られたRACK1は、MTK1の活性化からp38/JNKを介したアポトーシスを引き起こすが、ストレス顆粒はRACK1を顆粒内に隔離しアポトーシスを抑制することが知られる。TM4SF1AS1の過剰発現により形成されたストレス顆粒にRACK1が局在したことから、がん細胞におけるTM4SF1AS1によるストレス顆粒の機能として、生存に不利に働くタンパク質や転写産物を隔離しその機能の阻害や翻訳を抑制することが考えられた。 そこでTM4SF1AS1と相互作用し翻訳抑制を受ける可能性のあるRNA分子の探索を、ChIRP RNA-seqにより試みた。結果585個の候補が得られ、その三分の一がmRNAに該当した。Gene Ontology解析を行った結果、アポトーシスに関連するmRNAがエンリッチしていた。一部のアポトーシス関連mRNAがTM4SF1AS1の標的となり翻訳抑制を受ける可能性があると考えられることから、さらなる解析を進める。

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