Identification of microRNA underying the common pathogenic mechanism of lung cancer and interstitial pneumonia and establishment of a basis for its therapeutic application

• Project/Area Number: 17K09671
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tokyo Medical University
• Principal Investigator: Nobuyuki Koyama 東京医科大学, 医学部, 教授 (30353460)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 非小細胞肺癌 / 間質性肺炎 / マイクロRNA / 上皮間葉転換 / 筋線維芽細胞分化 / 転移 / 浸潤 / 肺線維化 / 網羅的発現解析 / 疾患モデルマウス / 間質性肺炎合併非小細胞肺癌 / 肺癌 / 共通発症機序 / モデルマウス

Outline of Final Research Achievements

Both lung cancer and interstitial pneumonia are refractory and highly comorbid diseases. In the present study, we identified miR-X of microRNA (miRNA) that commonly suppressed the mechanism underlying the development and progression of both diseases.
Using comprehensive miRNA expression analysis, we found commonly decreased expression levels of miR-X in lung cancer and interstitial pneumonia tissues in patients with comorbid lung cancer and interstitial pneumonia, compared to those in healthy lung and lung cancer tissues in patients with lung cancer without interstitial pneumonia.　Overexpression of miR-X suppressed cell growth and epithelial-mesenchymal transition involved in cancer metastasis and invasion in lung cancer cell lines and inhibited differentiation of fibroblasts to myofibroblasts as an indicator of pulmonary fibrogenesis. These findings shown in in vitro assays were confirmed in in vivo assays using disease model mice.

Academic Significance and Societal Importance of the Research Achievements

難治性疾患である肺癌と間質性肺炎は高率に合併し、間質性肺炎合併肺癌は治療選択肢が乏しく、予後不良である。本研究で同定したmiR-Xは、肺癌と間質性肺炎の発症・進展を共通に抑制した。miR-Xの同定と細胞および疾患モデルマウスを用いたmiR-X効果の検証により、肺癌と間質性肺炎の新たな発症・進展機序が明らかになるとともに、両疾患のみならず間質性肺炎合併肺癌に対するmiR-Xを用いた新たな治療の開発、臨床応用への基盤となることが期待できる。さらに、miR-Xは短鎖非コードRNAであるマイクロRNA（miRNA）であり、肺癌、間質性肺炎に対するこれまでにはない治療モダリティーの開発が期待される。

Research Products

• [Journal Article] Serum C-reactive protein level predicts clinical outcomes in patients with non-small cell lung cancer harboring EGFR mutations. (2020)
  • Author(s): Koyama N, Aoshiba K, Nakamura H.
  • Journal Title: Cancer Invest. Volume: 38 Issue: 2 Pages: 122-129
  • DOI: 10.1080/07357907.2020.1721522
  • Peer Reviewed
• [Journal Article] Pulmonary mucoepidermoid carcinoma arising in a patient with Kartagener syndrome. (2020)
  • Author(s): Nagai Y, Koyama N, Iwai Y, Tsubochi H, Hiruta M, Mizushina Y, Koyama S, Ishikawa Y, Hagiwara K
  • Journal Title: BMC Pulm Med. Volume: 20(1) Issue: 1 Pages: 93-93
  • DOI: 10.1186/s12890-020-1133-y
  • Peer Reviewed / Open Access
• [Journal Article] A case of miliary tuberculosis presenting as massive hepatosplenomegaly and fatal hepatic failure. (2020)
  • Author(s): Kawagoe J, Iwai Y, Kawamata G, Koyama N, Nakamura H, Aoshiba K.
  • Journal Title: ID Cases. Volume: 19 Pages: e00707-e00707
  • DOI: 10.1016/j.idcr.2020.e00707
  • Peer Reviewed / Open Access
• [Journal Article] Simultaneous metastasized primary unknown signet ring cell carcinoma of the cervical lymph node and mucoepidermoid carcinoma of the parotid gland as double cancers. (2020)
  • Author(s): Miyake K, Kondo T, Koyama N, Hirano H, Wakiya M, Takeda A, Iwasawa T, Kikawada N, Hanyu K, Ogawa Y, Tsukahara K.
  • Journal Title: Auris Nasus Larynx. Volume: 47 Issue: 1 Pages: 163-167
  • DOI: 10.1016/j.anl.2019.03.004
  • Peer Reviewed
• [Journal Article] Idiopathic pulmonary fibrosis in small cell lung cancer as a predictive factor for poor clinical outcome and risk of its exacerbation. (2019)
  • Author(s): Koyama N, Iwai Y, Nagai Y, Aoshiba K, Nakamura H.
  • Journal Title: PLOS ONE. Volume: 14 Issue: 8 Pages: e0221718-e0221718
  • DOI: 10.1371/journal.pone.0221718
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of nivolumab in 100 patients with recurrent or metastatic head and neck cancer a retrospective multicenter study. (2019)
  • Author(s): Okamoto I, Sato H, Kondo T, Koyama N, Fushimi C, Okada T, Miura K, Matsuki T, Yamashita T, Omura G, and Tsukahara K.
  • Journal Title: Acta otolaryngol Volume: 139 Issue: 10 Pages: 918-925
  • DOI: 10.1080/00016489.2019.1648867
  • Peer Reviewed
• [Journal Article] 非小細胞肺癌薬物療法の最新情報と今後の課題 (2019)
  • Author(s): 小山信之
  • Journal Title: 都薬雑誌 Volume: 41 Pages: 4-12
• [Journal Article] Hypercapnic tumor microenvironment confers chemoresistance to lung cancer cells by reprograming mitochondrial metabolism in vitro. (2019)
  • Author(s): Kikuchi R, Iwai Y, Tsuji T, Watanabe Y, Koyama N, Yamaguchi K, Nakamura H, Aoshiba K.
  • Journal Title: Free Radic Biol Med Volume: 134 Pages: 200-214
  • DOI: 10.1016/j.freeradbiomed.2019.01.014
  • Peer Reviewed
• [Journal Article] Pre-existing interstitial lung disease as a risk factor for pneumonitis associated with ramucirumab and paclitaxel in patients with gastric cancer: the impact of usual interstitial pneumonia (2018)
  • Author(s): Koyama N, Katayanagi S, Kawachi S.
  • Journal Title: PLOS ONE. Volume: 13 Issue: 6 Pages: e0198886-e0198886
  • DOI: 10.1371/journal.pone.0198886
  • Peer Reviewed
• [Journal Article] Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma (2018)
  • Author(s): Ko R, Shukuya T, Okuma Y, Tateishi K, Imai H, Iwasawa S, Miyauchi E, Fujiwara A, Sugiyama T, Azuma K, Muraki K, Yamasaki M, Tanaka H, Takashima Y, Soda S, Ishimoto O, Koyama N, Morita S, Kobayashi K, Nukiwa T, Takahashi K; North East Japan Study Group.
  • Journal Title: Oncologist Volume: unknown Issue: 10 Pages: 1210-1217
  • DOI: 10.1634/theoncologist.2017-0586
  • Peer Reviewed
• [Journal Article] Effectiveness of nanoparticle albumin-bound paclitaxel plus carboplatin in non-small cell lung cancer patients with malignant pleural effusion. (2018)
  • Author(s): Koyama N, Watanabe Y, Iwai Y, Nagai Y, Aoshiba K, Nakamura H.
  • Journal Title: Neoplasma. Volume: 65 Issue: 01 Pages: 132-139
  • DOI: 10.4149/neo_2018_170206n78
  • Peer Reviewed
• [Journal Article] High incidence and early onset of nivolumab-induced pneumonitis: four case reports and literature review (2018)
  • Author(s): Koyama N.、Iwase O.、Nakashima E.、Kishida K.、Kondo T.、Watanabe Y.、Takahashi H.、Umebayashi Y.、Ogawa Y.、Miura H.
  • Journal Title: BMC Pulmonary Medicine Volume: 18 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s12890-018-0592-x
  • Peer Reviewed / Open Access
• [Presentation] miR-4448は小細胞肺癌のEZH2による上皮間葉転換を介した腫瘍増殖機能を阻害する (2019)
  • Author(s): 小山信之、石川雄一、岩井悠希、青柴和徹、中村博幸、萩原弘一
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] Reciprocal effect of EZH2 and miR-4448 on tumor growth via epithelial mesenchymal transition in small cell lung cancer (2019)
  • Author(s): Koyama N, Ishikawa Y, Aoshiba K, Nakamura H, Hagiwara K.
  • Organizer: The 78th Annual Meeting of the Japanese Cancer Association
• [Presentation] Updated progression free survival (PFS) and survival (OS) of a Phase I/II Study of Nedaplatin and nab-Paclitaxel for Patients with Previously Untreated Advanced Squamous Cell Lung Cancer －KRSG 1302－ (2019)
  • Author(s): Ohyanagi F, Nagai Y, Kasai T, Koyama N, Kobayashi K, Hoshi E, Nakayama M, Mori K.
  • Organizer: 2019 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] High Level of serum C-reactive protein predicts poor outcome in EGFR-TKI-treated patients with EGFR-mutated NSCLC. (2019)
  • Author(s): Koyama N
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] A Phase I/II Study of Nedaplatin and nab-Paclitaxel for Patients with Previously Untreated Advanced Squamous cell Lung Cancer. (2019)
  • Author(s): Sugiyama T, Kasai T, Koyama N, Kobayashi K, Hoshi E, Nakayama M, Mori K.
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] 癌に対するラムシルマブ/パクリタキセル併用療法に伴う薬剤性肺障害の特徴 (2019)
  • Author(s): 小山信之、片柳創、青柴和徹、中村博幸
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] 肺癌細胞のエネルギー代謝を浪費させる新規治療薬の開発 (2019)
  • Author(s): 岩井悠希、菊池亮太、辻隆夫、小山信之、中村博幸、青柴和徹
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung cancer. (2019)
  • Author(s): Koyama N, Ishikawa Y, Iwai Y, Aoshiba K, Nakamura H, Hagiwara K.
  • Organizer: American Association for Cancer Research Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] 800/15-ESI-09 and HJC0197, known EPAC inhibitors, sensitize lung cancer cells to glucose starvation by uncoupling mitochondrial electron transport, leading to bioenergetics crisis. (2019)
  • Author(s): Iwai Y, Kikuchi R, Nakamura H, Koyama N, Hagiwara K, Aoshiba K.
  • Organizer: American Association for Cancer Research Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] EGFR遺伝子変異陽性非小細胞肺癌におけるEGFR-TKI効果予測因子としての血清CRP (2018)
  • Author(s): 小山信之、内田修、高橋秀暢
  • Organizer: 第59回日本肺癌学会学術集会
• [Presentation] Serum levels of C-reactive protein as a predictive factor for responses to EGFR-TKIs in patients with EGFR-mutated NSCLC. (2018)
  • Author(s): Koyama N.
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association
• [Presentation] 胃癌に対するラムシルマブ/パクリタキセル併用療法に伴う薬剤性肺臓炎の特徴 (2018)
  • Author(s): 小山信之、片柳創、河地茂行
  • Organizer: 第16回日本臨床腫瘍学会学術集会
• [Presentation] Extracellular acidosis inhibits glucose starvation-induced lung cancer cell death by suppressing overall metabolic rate. (2018)
  • Author(s): Iwai Y, Kikuchi R, Watanabe Y, Koyama N, Hagiwara K, Nakamura H, Aoshiba K.
  • Organizer: American Association for Cancer Research Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Clinicopathological characteristics of NSCLC patients with nivolumab-induced pneumonitis. (2017)
  • Author(s): Koyama N.
  • Organizer: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] 当院にてニボルマブ治療による肺障害を発症した非小細胞肺癌症例の臨床病理学的特徴 (2017)
  • Author(s): 小山信之、中嶋英治、渡辺恭孝、高橋秀暢、三浦弘之
  • Organizer: 第58回日本肺癌学会学術集会
• [Presentation] 当院のニボルマブ治療による肺障害発症例における臨床病理学的特徴 (2017)
  • Author(s): 小山信之、岩瀬理、中嶋英治、岸田功典、渡辺恭孝、高橋秀暢、三浦弘之
  • Organizer: 第15回日本臨床腫瘍学会学術集会