KITAJIMA Hiroshi

写真a

Affiliation

School of Medicine, Department of Molecular Biology

Job title

Assistant Professor
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Professional Memberships 【 display / non-display 】

  • 2017.11
    -
    Now

    The Molecular Biology Society of Japan

  • 2017.05
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    Now

    RNA Japan

  • 2017.02
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    Now

    The Japanese Society for Epigenetics

  • 2016.04
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    Now

    Japanese Cancer Association

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Research Areas 【 display / non-display 】

  • Life sciences   Tumor biology   non-coding RNA

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Affiliation 【 display / non-display 】

  • 札幌医科大学   医学部分子生物学講座   助教  

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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

  • 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

  • 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  2022.11  [International journal]

    　View Summary

    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  2022.10  [International journal]

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    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

  • 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

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Misc 【 display / non-display 】

  • Development of a new combinational epigenetic therapy of multiple myeloma

    石黒一也, 石黒一也, 北嶋洋志, 新沼猛, 石田禎夫, 丸山玲緒, 池田博, 山本英一郎, 山本英一郎, 甲斐正広, 佐々木泰史, 時野隆至, 仲瀬裕志, 鈴木拓

    日本癌学会学術総会抄録集(Web)   78th  2019

    J-GLOBAL

  • 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  2018.08

  • 胃がん発生に関与する長鎖non-coding RNAの同定

    北嶋 洋志, 丸山 玲緒, 山本 英一郎, 新沼 猛, 甲斐 正広, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    生命科学系学会合同年次大会 ( 生命科学系学会合同年次大会運営事務局 )  2017年度   [2P - 0828]  2017.12

  • 大腸がんにおけるDiacylglycerol kinase γのエピジェネティックな不活性化

    甲斐 正広, 山本 英一郎, 佐藤 亜紀子, 山野 泰穂, 新沼 猛, 北嶋 洋志, 原田 拓, 青木 敬則, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事 ( 日本癌学会 )  76回   J - 2093  2017.09

  • 大腸がんにおける腫瘍血管内皮関連遺伝子の同定

    萬 顕, 山本 英一郎, 沼田 有斗, 新沼 猛, 北嶋 洋志, 甲斐 正広, 青木 敬則, 若杉 英樹, 時野 隆至, 中瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事 ( 日本癌学会 )  76回   P - 2224  2017.09

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Industrial Property Rights 【 display / non-display 】

  • 長鎖ノンコーディングRNAを標的とするがん治療剤およびがん診断方法

    特許7319688

    北嶋洋志, 丸山玲緒, 山本英一郎, 鈴木拓

    Patent

  • 長鎖ノンコーディングＲＮＡを標的とするがん治療剤およびがん診断

    北嶋洋志, 丸山玲緒, 山本英一郎, 鈴木拓

    Patent

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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

  • 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

    Authorship： Principal investigator

    　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。

  • Revealing the function and the molecular network of a novel lncRNA associated with gastric cancer and gastritis

    Grant-in-Aid for Early-Career Scientists

    Project Year :

    2018.04
    -
    2020.03
     

    Kitajima Hiroshi

    　View Summary

    Gastric cancers (GCs) develop through Helicobacter Pylori-induced chronic gastritis. The involvement of long noncoding RNAs (lncRNAs) in inflammation-related carcinogenesis remains unclear. We have identified a lncRNA TM4SF1AS1, which promotes GC cell proliferation and tumor formation. To unravel pathways and molecular networks associated with TM4SF1AS1 in the tumorigenesis, we comprehensively screened a series of TM4SF1AS1-binding proteins. We identified many stress granule-associated molecules and found that TM4SF1AS1 promoted stress granule-like bodyformation in GC cells. Moreover, TM4SF1AS1 inhibited apoptosis mediated by stress-responsive MAPK. It suggested that TM4SF1AS1 might be a lncRNA link between tumorigenesis and stress granule and a potential therapeutic target.

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Presentations 【 display / non-display 】

  • 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

    Presentation date： 2021.09

    Event date：
    2021.09
    　
    　

  • 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

    Presentation date： 2020.10

    Event date：
    2020.10
    　
    　

  • 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

    Presentation date： 2018.08

    Event date：
    2018.08
    　
    　

  • 胃がん発生に関与する長鎖non-coding RNAの同定

    北嶋 洋志, 丸山 玲緒, 山本 英一郎, 新沼 猛, 甲斐 正広, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    生命科学系学会合同年次大会  生命科学系学会合同年次大会運営事務局

    Presentation date： 2017.12

    Event date：
    2017.12
    　
    　

  • SMOC1のエピジェネティックなサイレンシングは大腸鋸歯状腺腫の発育進展に関連する

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

    日本癌学会総会記事  日本癌学会

    Presentation date： 2017.09

    Event date：
    2017.09
    　
    　

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