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

• Project/Area Number: 18K15220
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Kitajima Hiroshi 札幌医科大学, 医学部, 助教 (90777971)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 胃がん / 長鎖non-coding RNA / ストレス顆粒 / lncRNA / 慢性炎症 / 炎症

Outline of Final Research Achievements

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.

Academic Significance and Societal Importance of the Research Achievements

これまでlncRNA研究において慢性炎症とがんに関わるlncRNAの報告は少なく、 TM4SF1AS1のようにストレス顆粒と発がんを結びつけるlncRNAの報告はない。また、TM4SF1AS1の阻害は胃がんのみならず他のがん細胞においても細胞増殖の抑制効果があることを確認している。TM4SF1AS1のがん遺伝子的機能とその作用機序は、様々ながんに共通する可能性があり、新たながん治療標的分子となりうることが今後期待される。以上より、本研究の成果は学術的にも社会的にも意義は高いものと考える。

Research Products

• [Journal Article] Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis. (2021)
  • Author(s): Ishiguro K, Kitajima H, Niinuma T, Maruyama R, Nishiyama N, Ohtani H, Sudo G, Toyota M, Sasaki H, Yamamoto E, Kai M, Nakase H, Suzuki H.
  • Journal Title: Cell Death Discovery Volume: 7 Issue: 1 Pages: 7-7
  • DOI: 10.1038/s41420-020-00400-0
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of AEBP1 in endothelial cells promotes tumor angiogenesis in colorectal cancer (2020)
  • Author(s): Yorozu Akira、Yamamoto Eiichiro、Niinuma Takeshi、Tsuyada Akihiro、Maruyama Reo、Kitajima Hiroshi、Numata Yuto、Kai Masahiro、Sudo Gota、Kubo Toshiyuki、Nishidate Toshihiko、Okita Kenji、Takemasa Ichiro、Nakase Hiroshi、Sugai Tamotsu、Takano Kenichi、Suzuki Hiromu
  • Journal Title: Cancer Science Volume: － Issue: 5 Pages: 1631-1644
  • DOI: 10.1111/cas.14360
  • Peer Reviewed / Open Access
• [Journal Article] UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells (2019)
  • Author(s): Niinuma Takeshi、Kitajima Hiroshi、Kai Masahiro、Yamamoto Eiichiro、Yorozu Akira、Ishiguro Kazuya、Sasaki Hajime、Sudo Gota、Toyota Mutsumi、Hatahira Tomo、Maruyama Reo、Tokino Takashi、Nakase Hiroshi、Sugai Tamotsu、Suzuki Hiromu
  • Journal Title: Clinical Epigenetics Volume: 11 Issue: 1 Pages: 70-70
  • DOI: 10.1186/s13148-019-0668-3
  • Peer Reviewed / Open Access
• [Journal Article] Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway. (2018)
  • Author(s): Aoki H, Yamamoto E, Yamano HO, Sugai T, Kimura T, Tanaka Y, Matsushita HO, Yoshikawa K, Takagi R, Harada E, Nakaoka M, Yoshida Y, Harada T, Sudo G, Eizuka M, Yorozu A, Kitajima H, Niinuma T, Kai M, Nojima M, Suzuki H, Nakase H.
  • Journal Title: Dig Dis Sci. Volume: 15 Issue: 7 Pages: 1920-1928
  • DOI: 10.1007/s10620-018-5016-5
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer (2018)
  • Author(s): Shindo Tetsuya、Niinuma Takeshi、Nishiyama Naotaka、Shinkai Nobuo、Kitajima Hiroshi、Kai Masahiro、Maruyama Reo、Tokino Takashi、Masumori Naoya、Suzuki Hiromu
  • Journal Title: Oncotarget Volume: 9 Issue: 36 Pages: 24457-24469
  • DOI: 10.18632/oncotarget.25326
  • Peer Reviewed / Open Access
• [Journal Article] Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1 (2018)
  • Author(s): Nishiyama K、Maruyama R、Niinuma T、Kai M、Kitajima H、Toyota M、Hatanaka Y、Igarashi T、Kobayashi J、Ogi K、Dehari H、Miyazaki A、Yorozu A、Yamamoto E、Idogawa M、Sasaki Y、Sugai T、Tokino Takashi、Hiratsuka H、Suzuki H
  • Journal Title: Cell Death & Disease Volume: 9 Issue: 8 Pages: 826-826
  • DOI: 10.1038/s41419-018-0893-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment (2018)
  • Author(s): Wakasugi H, Takahashi H, Niinuma T, Kitajima H, Oikawa R, Matsumoto N, Takeba Y, Otsubo T, Takagi M, Ariizumi Y, Suzuki M, Okuse C, Iwabuchi S, Nakano M, Akutsu N, Kang JH, Matsui T, Yamada N, Sasaki H, Yamamoto E, Kai M, Sasaki Y, Sasaki, Tanaka, Yotsuyanagi, Tsutsumi, Yamamoto, Tokino T , Nakase H, Suzuki H, Itoh F
  • Journal Title: Cancer Letters Volume: 434 Pages: 91-100
  • DOI: 10.1016/j.canlet.2018.07.019
  • Peer Reviewed
• [Journal Article] Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors (2018)
  • Author(s): Harada T、Yamamoto E、Yamano HO、Aoki H、Matsushita HO、Yoshikawa K、Takagi R、Harada E、Tanaka Y、Yoshida Y、Eizuka M、Yorozu A、Sudo G、Kitajima H、Niinuma T、Kai M、Sasaki Y、Tokino Takashi、Sugai T、Nakase H、Suzuki H
  • Journal Title: Journal of Gastroenterology Volume: 53 Issue: 12 Pages: 1241-1252
  • DOI: 10.1007/s00535-018-1481-z
  • Peer Reviewed / Open Access
• [Journal Article] DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling (2018)
  • Author(s): Ishiguro Kazuya、Kitajima Hiroshi、Niinuma Takeshi、Ishida Tadao、Maruyama Reo、Ikeda Hiroshi、Hayashi Toshiaki、Sasaki Hajime、Wakasugi Hideki、Nishiyama Koyo、Shindo Tetsuya、Yamamoto Eiichiro、Kai Masahiro、Sasaki Yasushi、Tokino Takashi、Nakase Hiroshi、Suzuki Hiromu
  • Journal Title: Haematologica Volume: 104 Issue: 1 Pages: 155-165
  • DOI: 10.3324/haematol.2018.191262
  • Peer Reviewed / Open Access
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNA結合タンパク質の探索 (2021)
  • Author(s): 北嶋洋志、丸山玲緒、山本英一郎、新沼 猛、甲斐正広、仲瀬裕志、時野隆至、鈴木 拓
  • Organizer: 第14回 日本エピジェネティクス研究会年会
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定と解析 (2021)
  • Author(s): 北嶋洋志
  • Organizer: 令和2年度 若手支援研究成果発表会 コホート・生体試料支援プラットフォーム
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定 (2020)
  • Author(s): 北嶋洋志、丸山玲緒、高澤 啓、新沼 猛、山本英一郎、甲斐正広、時野隆至、小山内誠、仲瀬裕志、鈴木 拓
  • Organizer: 第42回 日本分子生物学会年会
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定 (2020)
  • Author(s): 北嶋洋志、丸山玲緒、高澤 啓、新沼 猛、山本英一郎、甲斐正広、時野隆至、小山内誠、仲瀬裕志、鈴木 拓
  • Organizer: 第79回 日本癌学会学術総会
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNA結合タンパク質の探索 (2019)
  • Author(s): 北嶋洋志，丸山玲緒，高澤啓，山本英一郎，新沼猛，甲斐正広，仲瀬裕志，時野隆至，鈴木拓
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 慢性胃炎および胃がん関連長鎖non-coding RNAの同定と機能解析 (2019)
  • Author(s): 北嶋洋志，丸山玲緒，新沼猛，山本英一郎，高澤啓，甲斐正広，時野隆至，仲瀬裕志，鈴木拓
  • Organizer: 第120回北海道癌談話会例会
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定と機能解析 (2019)
  • Author(s): 北嶋洋志，丸山玲緒，高澤啓，山本英一郎，新沼猛，甲斐正広，時野隆至，仲瀬裕志，鈴木拓
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 胃がん関連長鎖non-coding RNAの同定と機能解析 (2018)
  • Author(s): 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
  • Organizer: 第12回日本エピジェネティクス研究年会
• [Presentation] 慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定と機能解析 (2018)
  • Author(s): 北嶋洋志、丸山玲緒、山本英一郎、新沼猛、甲斐正広、佐々木泰史、時野隆至、仲瀬裕志、鈴木拓
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 慢性胃炎および胃がん関連長鎖non-coding RNAの同定と機能解析 (2018)
  • Author(s): 北嶋洋志、丸山玲緒、山本英一郎、新沼猛、甲斐正広、高澤啓、時野隆至、仲瀬裕志、鈴木 拓
  • Organizer: 第41回日本分子生物学会年会