新沼 猛 (ニイヌマ タケシ)

写真a

所属

医学部 分子生物学講座

職名

講師

ホームページ

https://kaken.nii.ac.jp/d/r/60708113.ja.html

経歴 【 表示 / 非表示

  • 2021年06月
    -
    継続中

    札幌医科大学   医学部 分子生物学講座   講師

研究分野 【 表示 / 非表示

  • ライフサイエンス   消化器内科学  

 

論文 【 表示 / 非表示

  • 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年03月  [国際誌]

     概要を見る

    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

  • 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年08月  [国際誌]

     概要を見る

    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年07月

     概要を見る

    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

  • Serum amyloid A1 recruits neutrophils to the invasive front of T1 colorectal cancers.

    Ayano Yoshido, Gota Sudo, Akira Takasawa, Hironori Aoki, Hiroshi Kitajima, Eiichiro Yamamoto, Takeshi Niinuma, Taku Harada, Toshiyuki Kubo, Hajime Sasaki, Kazuya Ishiguro, Akira Yorozu, Masahiro Kai, Akio Katanuma, Hiro-O Yamano, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

    Journal of gastroenterology and hepatology   38 ( 2 ) 301 - 310  2022年11月  [国際誌]

     概要を見る

    BACKGROUND AND AIM: The tumor microenvironment plays an essential role in the development and progression of colorectal cancer (CRC). We recently reported that crosstalk between CRC cells and tumor-associated macrophages (TAMs) via serum amyloid A1 (SAA1) promotes invasion by T1 CRCs. In the present study, we aimed to clarify the role of neutrophils in early CRCs. METHODS: Immunohistochemical analysis of CD66b, chemokine CXC motif ligand 8 (CXCL8 or interleukin-8, IL-8) and matrix metalloproteinase-9 (MMP-9) was performed using primary T1 CRCs (n = 49). The HL-60 human promyelocytic leukemia cell line and THP-1 human monocytic leukemia cell line were used to obtain neutrophil-like and macrophage-like cells, respectively. Boyden chamber assays were used to analyze cell migration and invasion, and quantitative RT-PCR was used to analyze gene expression. RESULTS: Immunohistochemical analysis revealed accumulation of neutrophils at the SAA1-positive invasive front of T1 CRCs. Experiments using HL-60 cells suggested that treatment with SAA1 induced neutrophil migration and expression of CXCL8 and MMP-9 in neutrophils and that neutrophils promote CRC cell migration and invasion. Immunohistochemistry confirmed accumulation of CXCL8- or MMP-9-positive neutrophils at the SAA1-positive invasive front of T1 CRCs. Moreover, co-culture experiments using CRC, THP-1 and HL-60 cells suggested that CRC cells activated by macrophages upregulate CXCL8 and MMP-9 in neutrophils. CONCLUSIONS: Our results suggest that interplay between macrophages and CRC cells leads to recruitment of neutrophils to the invasive front of T1 CRCs and that SAA1 secreted by CRC cells activate neutrophils to promote invasion.

    DOI PubMed

  • CXCL12 is expressed by skeletal muscle cells in tongue oral squamous cell carcinoma.

    Akira Yorozu, Shohei Sekiguchi, Akira Takasawa, Fumika Okazaki, Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Masahiro Kai, Mutsumi Toyota, Yui Hatanaka, Koyo Nishiyama, Kazuhiro Ogi, Hironari Dehari, Kazufumi Obata, Makoto Kurose, Atsushi Kondo, Makoto Osanai, Akihiro Miyazaki, Kenichi Takano, Hiromu Suzuki

    Cancer medicine   12 ( 5 ) 5953 - 5963  2022年10月  [国際誌]

     概要を見る

    BACKGROUND: The CXCL12/CXCR4 axis plays a pivotal role in the progression of various malignancies, including oral squamous cell carcinoma (OSCC). In this study, we aimed to clarify the biological and clinical significance of CXCL12 in the tumor microenvironment of OSCCs. METHODS: Publicly available single-cell RNA-sequencing (RNA-seq) datasets were used to analyze CXCL12 expression in head and neck squamous cell carcinomas (HNSCC). Immunohistochemical analysis of CXCL12, α-smooth muscle antigen (α-SMA), fibroblast activation protein (FAP) and CD8 was performed in a series of 47 surgically resected primary tongue OSCCs. Human skeletal muscle cells were co-cultured with or without OSCC cells, after which CXCL12 expression was analyzed using quantitative reverse-transcription PCR. RESULTS: Analysis of the RNA-seq data suggested CXCL12 is abundantly expressed in stromal cells within HNSCC tissue. Immunohistochemical analysis showed that in grade 1 primary OSCCs, CXCL12 is expressed in both tumor cells and muscle cells. By contrast, grade 3 tumors were characterized by disruption of muscle structure and reduced CXCL12 expression. Quantitative analysis of CXCL12-positive areas within tumors revealed that reduced CXCL12 expression correlated with poorer overall survival. Levels of CXCL12 expression tended to inversely correlate α-SMA expression and positively correlate with infiltration by CD8+ lymphocytes, though these relations did not reach statistical significance. CXCL12 was significantly upregulated in muscle cells co-cultured with OSCC cells. CONCLUSION: Our results suggest that tongue OSCC cells activate CXCL12 expression in muscle cells, which may contribute to tumor progression. However, CXCL12 is reduced in advanced OSCCs due to muscle tissue destruction.

    DOI PubMed

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Misc 【 表示 / 非表示

  • 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年02月

    研究発表ペーパー・要旨(国際会議)  

  • 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年10月

    研究発表ペーパー・要旨(国際会議)  

  • 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年09月

  • 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 )  79回   PJ14 - 1  2020年10月

  • 臨床医学の最新情報 がんのnon-coding RNA異常およびエピゲノム異常の解析とその応用

    鈴木 拓, 新沼 猛, 北嶋 洋志, 山本 英一郎, 甲斐 正広, 高橋 秀明, 伊東 文生

    電気泳動 ( 日本電気泳動学会 )  62 ( Suppl. ) s23 - s23  2018年08月

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共同研究・競争的資金等の研究課題 【 表示 / 非表示

  • 大腸低分化腺がんにおけるSAA1の分子機能解明と診断・治療への応用

    基盤研究(C)

    研究期間:

    2022年04月
    -
    2025年03月
     

    青木 敬則, 高澤 啓, 山本 英一郎, 新沼 猛

  • 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)

    研究期間:

    2022年04月
    -
    2025年03月
     

    鈴木 拓, 仲瀬 裕志, 新沼 猛, 北嶋 洋志

  • 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)

    研究期間:

    2021年04月
    -
    2024年03月
     

    新沼 猛, 鈴木 拓

     研究概要を見る

    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。

  • 大腸癌進展に関与するエピゲノムおよびlncRNAの同定と診断・治療への応用

    基盤研究(C)

    研究期間:

    2018年04月
    -
    2021年03月
     

    新沼 猛, 鈴木 拓

     研究概要を見る

    本研究においてはTCGAデータなどのデータベースを用いて、消化管癌の正常と腫瘍部におけるlncRNAの発現比較を行った。様々な抽出方法により数個のlncRNAに着目し解析を行った。特にlncXにおける解析においては、そのノックダウンが腫瘍細胞のアポトーシスを誘導する事や遺伝子発現マイクロアレイ解析やqRT-PCR解析、ウエスタンブロット法により細胞周期関連遺伝子群の発現が低下することが明らかとなった。細胞周期遺伝子群の発現を制御するCDEドメインを用いたレポーターアッセイからはlncXがDREAM complexによる発現抑制ではなく、転写活性化に関連していることが示唆された。

  • 消化管がん進展過程におけるエピゲノム異常とnoncodingRNA発現の統合解析

    若手研究(B)

    研究期間:

    2016年04月
    -
    2018年03月
     

    新沼 猛, 鈴木 拓

     研究概要を見る

    消化管がん転移に寄与するlncRNAをTCGAの大腸がんの遺伝子発現データであるCOADREAD exonexpressionを用いて抽出した。正常大腸より発現が高く、リンパ節転移陽性群で転移陰性群より発現が高いlncRNAから21遺伝子を解析の対象とした。選択したlncRNAの発現を大腸がん細胞で検討し、大腸がんで正常より発現が上昇しているlncRNAとしてDUXAP8, DUXAP10を抽出した。DUXAP10をノックダウンは細胞増殖を有意に抑制し、スクラッチアッセイでは遊走能の抑制が認められた。以上よりDUXAP10は大腸癌において増殖、遊走能に関与するlncRNAと考えられた。

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