選択的ピロリ菌除菌治療への基盤創造を目的としたピロリ菌東アジア株の層別化

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19K16707
• Research Institution: Chiba University
• Principal Investigator: 福世 真樹 千葉大学, 大学院医学研究院, 助教 (40639085)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ピロリ菌 / 胃癌 / DNAメチル化 / 発癌

Outline of Annual Research Achievements

ピロリ菌は胃がんの発がん細菌である.その発がん要因としてはIV型分泌装置を介してホスト細胞内に分泌されるCagAタンパクががんタンパクSHP2を活性化し 異常増殖シグナルを 生成すること等が分かっているが，非発がん型cagA株やcagA-株がいかにホスト細胞のゲノム変異・エピゲノム異常を引き起こし発がんに至 るのか，世界中で研究が進むものの詳細は明らかになっていない.ピロリ菌感染は慢性胃炎を経て萎縮性胃炎ないし腸上皮化生を誘発し，胃がん発がんリスクを 上昇させるというデメリットを持つが，胃酸を抑え逆流性食道炎を抑えことによって食道胃接合部がんを抑制するというメリットも持つ.また，除菌に用いる薬 剤による副作用，耐性菌の出現といったリスクもある.このため，ピロリ菌は除菌すべきでないという立場からの提言もあり，除菌すべきピロリ菌と除菌すべき でないピロリ菌を分類する必要性がある.そこで本研究では，発がんハイリスクピロリ菌の選択的除菌治療への基盤を創生する事を 目的として，ヒトゲノム データとピロリ菌ゲノム・DNAメチル化(メチローム)データを統合する申請者のオミックス解析技術を駆使して，ピロリ菌東アジア株110 株の層別化により除菌 すべきピロリ菌の特徴解明を行った.
(A)これまでに得られていた全ゲノムデータを元に集団構造解析を行い,東アジアのピロリ菌亜集団hspEAsia内に,低発生率地域と高発生率地域の間の地理的分化を明らかにした．
(B)これまでの解析でがん変異への関連が明らかになっているピロリ菌の持つ「ある制限酵素」について，去年度構築した大腸菌での発現系を用いた変異誘導実験を行い，全ゲノムを用いた変異解析を行った．

Research Products

• [Int'l Joint Research] National Cancer Institute (NCI)/New England Biolabs (NEB)(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: National Cancer Institute (NCI)/New England Biolabs (NEB)
• [Journal Article] Genomic differentiation within East Asian Helicobacter pylori (2022)
  • Author(s): You Yuanhai、Thorell Kaisa、He Lihua、Yahara Koji、Yamaoka Yoshio、Cha Jeong-Heon、Murakami Kazunari、Katsura Yukako、Kobayashi Ichizo、Falush Daniel、Zhang Jianzhong、TEAMHp
  • Journal Title: Microbial Genomics Volume: 8 Pages: 1~14
  • DOI: 10.1099/mgen.0.000676
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PHLDA3 Is an Important Downstream Mediator of p53 in Squamous Cell Carcinogenesis (2022)
  • Author(s): Saito Megumi、Sada Akane、Fukuyo Masaki、Aoki Kiyono、Okumura Kazuhiro、Tabata Yuko、Chen Yu、Kaneda Atsushi、Wakabayashi Yuichi、Ohki Rieko
  • Journal Title: Journal of Investigative Dermatology Volume: 142 Pages: 1040～1049.e8
  • DOI: 10.1016/j.jid.2021.09.007
  • Peer Reviewed
• [Journal Article] Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates (2021)
  • Author(s): Tuan V P、Yahara K、Dung H D Q、Binh T T、Huu T P、Tri T D、Thuan N P M、Khien V V、Trang T T H、Phuc B H、Tshibangu-Kabamba E、Matsumoto T、Akada J、Suzuki R、Okimoto T、Kodama M、Murakami K、Yano H、Fukuyo M、Takahashi N、Kato M、Nishiumi S、Azuma T、Ogura Y、Hayashi T、Toyoda A、Kobayashi I、Yamaoka Y
  • Journal Title: Microbial Genomics Volume: 7 Pages: 1~17
  • DOI: 10.1099/mgen.0.000680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of clonal immunoglobulin λ light-chain gene rearrangements in AL amyloidosis using next-generation sequencing (2021)
  • Author(s): Kimura K、Tsukamoto S、Miyazaki K、Kawajiri-Manako C、Ishii A、Rahmutulla B、Fukuyo M、Oshima-Hasegawa N、Mitsukawa S、Takeda Y、Mimura N、Takeuchi M、Ohwada C、Iseki T、Matsusaka K、Sanada M、Yokote K、Kaneda A、Ishida T、Suzuki K、Nakaseko C、Sakaida E
  • Journal Title: Experimental Hematology Volume: 101-102 Pages: 34～41.e4
  • DOI: 10.1016/j.exphem.2021.08.001
  • Peer Reviewed / Open Access
• [Journal Article] Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B‐cell lymphoma in a Japanese cohort (2021)
  • Author(s): Mishina T、Oshima‐Hasegawa N、Tsukamoto S、Fukuyo M、Kageyama H、Muto T、Mimura N、Rahmutulla B、Nagai Y、Kayamori K、Hino Y、Mitsukawa S、Takeda Y、Ohwada C、Takeuchi M、Tsujimura H、Iseki T、Nakaseko C、Ikeda J、Itami M、Yokote K、Ohara O、Kaneda A、Sakaida E
  • Journal Title: British Journal of Haematology Volume: 195 Pages: 731～742
  • DOI: 10.1111/bjh.17765
  • Peer Reviewed
• [Journal Article] Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein‐Barr virus?positive gastric cancer (2021)
  • Author(s): Li Wenzhe、Okabe Atsushi、Usui Genki、Fukuyo Masaki、Matsusaka Keisuke、Rahmutulla Bahityar、Mano Yasunobu、Hoshii Takayuki、Funata Sayaka、Hiura Nobuhiro、Fukayama Masashi、Tan Patrick、Ushiku Tetsuo、Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 112 Pages: 3349～3362
  • DOI: 10.1111/cas.14978
  • Peer Reviewed / Open Access
• [Journal Article] Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis (2021)
  • Author(s): Hata Atsushi、Nakajima Takahiro、Matsusaka Keisuke、Fukuyo Masaki、Nakayama Manabu、Morimoto Junichi、Ito Yuki、Yamamoto Takayoshi、Sakairi Yuichi、Rahmutulla Bahityar、Ota Satoshi、Wada Hironobu、Suzuki Hidemi、Iwata Takekazu、Matsubara Hisahiro、Ohara Osamu、Yoshino Ichiro、Kaneda Atsushi
  • Journal Title: International Journal of Cancer Volume: 148 Pages: 3008～3018
  • DOI: 10.1002/ijc.33499
  • Peer Reviewed
• [Presentation] Activation of EHF and Wnt signaling via STAT3 phosphorylation by LMP2A in Epstein-Barr virus-positive gastric cancer. (2021)
  • Author(s): Atsushi Kaneda, Wenzhe Li, Atsushi Okabe, Genki Usui, Masaki Fukuyo, Keisuke Matsusaka, Bahityar Rahmutulla Nawai, Yasunobu Mano, Sayaka Funata, Takayuki Hoshii, Tetsuo Ushiku, Patrick Tan, Masashi Fukayama
  • Organizer: 第32回日本消化器癌発生学会
• [Presentation] Molecular mechanism of carcinogenesis induced by HPV insertion in head and neck squamous cell carcinoma. (2021)
  • Author(s): Masato Mima, Atsushi Okabe, Takuya Nakagawa, Tomoya Kurokawa, Satoru Kondo, Harue Mizokami, Masaki Fukuyo, Bahityar R. Nawai, Takayuki Hoshii, Kiyoshi Misawa, Atsushi Kaneda
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] H3K4 methyltransferase SETD1A regulates the mitochondrial respiration in acute myeloid leukemia. (2021)
  • Author(s): Takayuki Hoshii, Sota Kikuchi, Rahmutulla Bahityar, Masaki Fukuyo, Tomoaki Tanaka, Atsushi Kaneda
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Analyses of primary gastric cancer risk in a cohort of 4,257 asymptomatic subjects and accumulated DNA methylation. (2021)
  • Author(s): Genki Usui, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla Nawai, Eiji Sakai, Tetsuo Ushiku, Atsushi Kaneda
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] 無症候検診コホートを対象とした胃発癌リスク因子の探索と胃粘膜に蓄積したDNAメチル化の解析 (2021)
  • Author(s): Genki Usui, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla Nawai, Eiji Sakai, Toshiaki Gunji, Nobuyuki Matsuhashi, Teppei Morikawa, Tetsuo Ushiku, Atsushi Kaneda
  • Organizer: 第32回日本消化器癌発生学会
• [Presentation] Tissue-wide analysis of chromatin structural aberrations induced by oncovirus infection. (2021)
  • Author(s): Atsushi Okabe, Takahiro Fujii, Harue Mizokami, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Atsushi Kaneda
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Heterochromatin disruption and chromatin structural rewiring induced by Epstein-Barr virus infection in gastric adenocarcinoma. (2021)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Takayuki Hoshii, Bahityar Rahmutulla, Genki Usui, Teru Kanda, Tetsuo Ushiku, Masashi Fukayama, Patrick Tan, Atsushi Kaneda
  • Organizer: 19thInternational Symposium on Epstein-Barr Virus and associated diseases.