RNA modifications of human tumors

• Project/Area Number: 16K15256
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Sugimura Haruhiko 浜松医科大学, 医学部, 教授 (00196742)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: RNA修飾 / 肺がん / m6A / WTAP / METTL3 / METTL14 / FTO / ALKBH5 / ヒトがん / 6 methyl adenine / YTHFD1 / YTHFD2 / DNA付加体 / RNA付加体 / RNA塩基修飾酵素 / アダクトミクス

Outline of Final Research Achievements

m6A measurement in human cancer tissue revealed m6A is relatively abundant in tumor portion of the lung and high m6A/A was related to the worse prognosis of the lung cancer. To elucidate the biological basis of this observation, modifying enzymes METTL14, METTL3, WTAP, FTO, ALKBH5, YTHDF1, YTHDF2 expression were investigated in 8 lung cancer cell lines and immortalized bronchial epithelium. Among them, WTAP, which is not expressed in immortalized bronchial epithelium and over expressed in lung cancer cell lines was investigated on its effect of siRNA and enforced overexpresssion. SiRNA experiment showed growth inhibition and decrease of m6A/A whereas over expression induced growth promotion. Immunoprecipitation analysis confirm its modification on EGFR 3UTR mA. Finally using our clinical cohort of 642 lung cancer cases, expression of WTAP in human lung cancer tissues are related to the prognosis including performance status and overall survival.

Research Products

• [Journal Article] Distinctive characteristics and prognostic significance of interstitial pneumonia with autoimmune features in patients with chronic fibrosing interstitial pneumonia. (2018)
  • Author(s): Yoshimura K, Kono M, Enomoto Y, Nishimoto K, Oyama Y, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Sumikawa H, Johkoh T, Colby TV, Sugimura H, Suda T.
  • Journal Title: Respiratory Medicine Volume: 137 Pages: 167-175
  • DOI: 10.1016/j.rmed.2018.02.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Heterogeneous MET gene copy number and EGFR mutation elicit discordant responses to crizotinib between primary and metastatic lesions in erlotinib-resistant lung adenocarcinoma. (2018)
  • Author(s): Yoshimura K, Karayama M, Inoue Y, Kahyo T, Inui N, Maekawa M, Sugimura H, Suda T
  • Journal Title: Lung Cancer Volume: pii: S0169-5002(18) Pages: 30305-2
  • DOI: 10.1016/j.lungcan.2018.03.016
  • Peer Reviewed / Open Access
• [Journal Article] Distinct prognostic roles and heterogeneity of TTF1 copy number and TTF1 protein expression in non-small cell lung cancer. (2018)
  • Author(s): Yoshimura K, Sugimura H
  • Journal Title: Genes Chromosomes Cancer Volume: 56 Issue: 7 Pages: 570-581
  • DOI: 10.1002/gcc.22461
  • Peer Reviewed
• [Journal Article] Characterization of V-set and immunoglobulin domain containing 1 exerting a tumor suppressor function in gastric, lung, and esophageal cancer cells (2017)
  • Author(s): Inoue Yusuke、Matsuura Shun、Yoshimura Katsuhiro、Iwashita Yuji、Kahyo Tomoaki、Kawase Akikazu、Tanahashi Masayuki、Maeda Matsuyoshi、Ogawa Hiroshi、Inui Naoki、Funai Kazuhito、Shinmura Kazuya、Niwa Hiroshi、Suda Takafumi、Sugimura Haruhiko
  • Journal Title: Cancer Science Volume: 108 Issue: 8 Pages: 1701-1714
  • DOI: 10.1111/cas.13295
  • Peer Reviewed
• [Journal Article] Successful crizotinib monotherapy in EGFR-mutant lung adenocarcinoma with acquired MET amplification after erlotinib therapy. (2017)
  • Author(s): Yoshimura K, Sugimura H et al.
  • Journal Title: Respir Med Case Rep. Volume: 20 Pages: 160-163
  • DOI: 10.1016/j.rmcr.2017.02.009
  • Peer Reviewed
• [Journal Article] WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma. (2017)
  • Author(s): Shinmura K, Kato H, Kawanishi Y, Igarashi H, Inoue Y, Yoshimura K, Nakamura S, Fujita H, Funai K, Tanahashi M, Niwa H, Ogawa H, Sugimura H
  • Journal Title: Mol Carcinog Volume: 印刷中 Issue: 8 Pages: 1984-1991
  • DOI: 10.1002/mc.22647
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High expression of Wls is associated with lymph node metastasis and advanced TNM stage in gastric carcinomas. (2017)
  • Author(s): Zhang W, Tao H, Chen X, Sugimura H, Wang J, Zhou P.
  • Journal Title: Pathol Int. Volume: 67 Issue: 3 Pages: 141-146
  • DOI: 10.1111/pin.12508
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. (2017)
  • Author(s): Inoue Y, Sugimura H. et al.
  • Journal Title: Oncotarget Volume: 8 Issue: 5 Pages: 8738-8751
  • DOI: 10.18632/oncotarget.14434
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Updates of immunnotherapy of lung cancer (2017)
  • Author(s): Sugimura Haruhiko
  • Organizer: Internaional conference of update of cancer prevention and research
  • Place of Presentation: Lucknow, India
  • Year and Date: 2017-02-14
  • Int'l Joint Research / Invited
• [Presentation] ヒト組織中のDNA付加体について (2016)
  • Author(s): 椙村春彦
  • Organizer: 平成28年度 日本環境変異学会 公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-05-18
  • Invited
• [Remarks] 浜松医科大学 腫瘍病理学
  • URL: https://www.hama-med.ac.jp/uni_education_igakubu_igaku_byouri1.html