Epigenetic abnormalities and reprogramming in epithelial-mesenchymal transition of lung adenocarcinoma

• Project/Area Number: 26293080
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Jichi Medical University
• Principal Investigator: Niki Toshiro 自治医科大学, 医学部, 教授 (90198424)
• Co-Investigator(Kenkyū-buntansha): 佐久間 裕司 札幌医科大学, 医学部, 准教授 (10364514) ; 吉本 多一郎 自治医科大学, 医学部, 講師 (20634166) ; 松原 大祐 自治医科大学, 医学部, 准教授 (80415554)
• Project Period (FY): 2014-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: 肺腺癌 / 上皮間葉転換 / エピジェネティックス / 分化形質 / メチル化 / 肺癌 / エピジェネティクス

Outline of Final Research Achievements

About 20-30% of lung adenocarcinoma show loss of expression of TTF-1 (thyroid-specific transcription factor-1), a master regulator of lung development and differentiation. These adenocarcinomas frequently present with either mucinous or poorly differentiated solid morphology, features of epithelial-mesenchymal transition, and lack targetable driver mutations, such as EGFR and ALK. In this study, we have revealed that these characteristics of this subset of lung cancer may be causally related with 1) abnormalities of histone modifier expression, 2) loss of expression of chromatin remodelers BRG1/BRM, and inactivation of TTF-1 gene itself by gene mutation or methylation.

Academic Significance and Societal Importance of the Research Achievements

ゲノム解析の進歩にも拘わらず、肺腺癌の20-30％では、治療標的となるドライバー変異がいまだ見出せていない。本研究によってもたらされた知見により、このような一群の肺腺癌におけるエピジェネティックス異常の重要性が認識され、今後の診断・治療開発に向けた研究が促進されることが期待される。

Research Products

• [Journal Article] Survivin knockdown induces senescence in TTF-1-expressing, KRAS-mutant lung adenocarcinomas. (2018)
  • Author(s): Sumi T, Hirai S, Yamaguchi M, Tanaka Y, Tada M, Yamada G, Hasegawa T, Miyagi Y, Niki T, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 33-46
  • DOI: 10.3892/ijo.2018.4365
  • Peer Reviewed / Open Access
• [Journal Article] Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells. (2018)
  • Author(s): Sumi T, Hirai S, Yamaguchi M, Tanaka Y, Tada M, Niki T, Takahashi H, Sakuma Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 501 Issue: 1 Pages: 253-258
  • DOI: 10.1016/j.bbrc.2018.04.230
  • Peer Reviewed
• [Journal Article] Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis. (2017)
  • Author(s): Yamaguchi M, Hirai S, Tanaka Y, Sumi T, Miyajima M, Mishina T, Yamada G, Otsuka M, Hasegawa T, Kojima T, Niki T, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: Laboratory Investigation Volume: 97 Pages: 232-242
  • Peer Reviewed
• [Journal Article] Establishment of highly metastatic KRAS mutant lung cancer cell sublines in long-term three-dimensional low attachment cultures. (2017)
  • Author(s): Nakano T, Kanai Y, Amano Y, Yoshimoto T, Matsubara D, Shibano T, Tamura T, Oguni S, Katashiba S, Ito T, Murakami Y, Fukayama M, Murakami T, Endo S, Niki T.
  • Journal Title: Plos One Volume: 12 Issue: 8 Pages: e0181342-e0181342
  • DOI: 10.1371/journal.pone.0181342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas. (2017)
  • Author(s): Matsubara D, Soda M, Yoshimoto T, Amano Y, Sakuma Y, Yamato A, Ueno T, Kojima S, Shibano T, Hosono Y, Kawazu M, Yamashita Y, Endo S, Hagiwara K, Fukayama M,Takahashi T, Mano H, Niki T.
  • Journal Title: Cancer Sci Volume: 108 Issue: 9 Pages: 1888-1896
  • DOI: 10.1111/cas.13313
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of YAP1 defines neuroendocrine differentiation of lung tumors. (2016)
  • Author(s): Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S, Isagawa T, Morikawa T, Shinozaki-Ushiku A, Goto Y, Nakano T, Tsuchiya T, Tsubochi H, Komura D, Aburatani H, Dobashi Y, Nakajima J, Endo S, Fukayama M, Sekido Y, Niki T, Murakami Y.
  • Journal Title: Cancer Science Volume: 107 Issue: 10 Pages: 1527-1538
  • DOI: 10.1111/cas.13013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype. (2016)
  • Author(s): Sakuma Y, Nishikiori H, Hirai S, Yamaguchi M, Yamada G, Watanabe A, Hasegawa T, Kojima T, Niki T, Takahashi H.
  • Journal Title: Lab Invest. Volume: 96 Issue: 4 Pages: 391-398
  • DOI: 10.1038/labinvest.2015.155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Frequent loss of the expression of multiple subunits of the SWI/SNF complex in large cell carcinoma and pleomorphic carcinoma of the lung. (2015)
  • Author(s): Yoshimoto T, Matsubara D, Nakano T, Tamura T, Endo S, Sugiyama Y, Niki T.
  • Journal Title: Pathology international Volume: 35 Issue: 11 Pages: 595-602
  • DOI: 10.1111/pin.12350
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma (2015)
  • Author(s): Shin Saito, Kazue Morishima, Takashi Ui, Hiroko Hoshino, Daisuke Matsubara, Shumpei Ishikawa, Hiroyuki Aburatani, Masashi Fukayama, Yoshinori Hosoya, Naohiro Sato, Alan K Lefor, Yoshikazu Yasuda and Toshiro Niki
  • Journal Title: BMC cancer Volume: 15 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s12885-015-1065-8
  • Peer Reviewed / Open Access
• [Journal Article] The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway. (2014)
  • Author(s): Ui T, Morishima K, Saito S, Sakuma Y, Fujii H, Hosoya Y, Ishikawa S, Aburatani H, Fukayama M, Niki T, Yasuda Y.
  • Journal Title: Oncol Rep. Volume: 31(2) Issue: 2 Pages: 619-24
  • DOI: 10.3892/or.2013.2899
  • Peer Reviewed / Open Access
• [Journal Article] Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. (2014)
  • Author(s): Ibrahim R, Matsubara D, Osman W, Morikawa T, Goto A, Morita S, Ishikawa S, Aburatani H, Takai D, Nakajima J, Fukayama M, Niki T, Murakami Y
  • Journal Title: Hum Pathol. Volume: 45 Issue: 7 Pages: 1397-405
  • DOI: 10.1016/j.humpath.2014.02.013
  • Peer Reviewed / Open Access
• [Journal Article] Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma. (2014)
  • Author(s): Saito S, Morishima K, Ui T, Matsubara D, Tamura T, Oguni S, Hosoya Y, Sata N, Lefor AT, Yasuda Y, Niki T.
  • Journal Title: Oncology Reports Volume: 32 Issue: 1 Pages: 348-354
  • DOI: 10.3892/or.2014.3216
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical analysis of the expression of E-cadherin and ZEB1 in non-small cell lung cancer. (2014)
  • Author(s): Matsubara D, Kishaba Y, Yoshimoto T, Sakuma Y, Sakatani T, Tamura T, Endo S, Sugiyama Y, Murakami Y, Niki T
  • Journal Title: Pathology International Volume: 64 Issue: 11 Pages: 560-568
  • DOI: 10.1111/pin.12214
  • Peer Reviewed / Open Access
• [Presentation] Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas. (2018)
  • Author(s): Matsubara D, Soda M, Yoshimoto T, Amano Y, Kihara A, Sakuma Y, Endo S, Hagiwara K, Fukayama M, Mano H, Niki T.
  • Organizer: Annual Meeting of American Association for Cancer Research
• [Presentation] Long-term, 3-dimensional spheroid culture: a putative model to study evolution of detached cancer cells in tumor metastasis. (2018)
  • Author(s): Shibano T, nakano T, Kanai Y, Yoshimoto T, Amano Y, Matsubara D, Murakami T, Endo S, Niki T.
  • Organizer: 17th Biennial Congress of Metastatic Research Society
• [Presentation] MUC21 is a candidate key molecule involved in the incohesive growth pattern of lung adenocarcinoma. (2018)
  • Author(s): Yoshimoto T, Matsubara D, Soda M, Amano Y, Kihara A, Nakano T, Shibano T, Endo S, Hagiwara K, Denda-Nagai K, Irimura T, Mano H, Niki T.
  • Organizer: 6th JCA-AACR Special Joint Conference
• [Presentation] 3D Low-Attachment Culture: A Putative Model for STAS And "Floating" Cancer Cells. (2017)
  • Author(s): Nakano T, Yoshimoto T, Kanai Y, Shibano T, Matsubara D, Endo S, Niki T.
  • Organizer: 18th World Conference of Lung Cancer
  • Int'l Joint Research
• [Presentation] Mutation of SWI/SNF Complex Genes Is Frequent in Poorly Differentiated, Mesenchymal-Like Lung Cancer without Major Driver Mutation. (2017)
  • Author(s): Yoshimoto T, Matsubara D, Niki T.
  • Organizer: 18th World Conference of Lung Cancer
  • Int'l Joint Research
• [Presentation] Establishment of Highly Metastatic Lung Cancer Cell Sublines in Long-term Three-dimensional Low Attachment Cultures. (2017)
  • Author(s): Nakano T, Kanai Y, Amano Y, Yoshimoto T, Matsubara D, Shibano T, Endo S, Niki T.
  • Organizer: 18th World Conference of Lung Cancer
  • Int'l Joint Research
• [Presentation] 系統的肺腺癌ゼノグラフトを用いた癌間質相互作用の解析 (2016)
  • Author(s): 吉本多一郎, 松原大祐, 河村大輔, 石川俊平, 仁木利郎
  • Organizer: 第５７回日本肺癌学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県、福岡市）
  • Year and Date: 2016-12-19
• [Presentation] 高橋 真依, 仁木 利郎, 松原 大祐, 吉本 多一郎 (2016)
  • Author(s): SWI/SNFのコアサブユニットBRMによる肺癌細胞の分化形質の制御とその分子機構
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 病理組織学的アプローチによるNon-TRUタイプ肺腺癌のNKX2-1遺伝子変異の同定 (2016)
  • Author(s): 松原 大祐、曽田 学, 吉本 多一郎, 天野 雄介, 上野 敏秀, 小島 進也, 間野 博行, 仁木 利郎
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 肺癌の上皮間葉転換におけるクロマチンリンモデリング因子異常の解析 (2016)
  • Author(s): 吉本多一郎、松原大祐、福嶋敬宜、仁木利郎
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 肺癌におけるYAP1 欠如と神経内分泌分化について． (2015)
  • Author(s): 松原大祐，伊東剛，田中一大，石川俊平，後藤悌，中野智之，土橋洋，中島淳，遠藤俊輔，深山正久，関戸好孝，仁木利郎，村上善則．
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Altered expressions of multiple subunits of the switch/sucrose non-fermenting (SWI/SNF) complex in Non-small cell lung cancer. (2015)
  • Author(s): Yoshimoto T, Matsubara D, Niki T.
  • Organizer: AACR special meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2015-09-24
  • Int'l Joint Research
• [Presentation] Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. (2014)
  • Author(s): ２４．Matsubara D, Ibrahim R, Osman W, Goto A, Morikawa T, Morita S, Ishikawa S, Aburatani H, Fukayama M, Niki T, Murakami Y.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] The HSP90 inhibitor 17-AAG improves chemoresistance of cisplatin-resistant esophageal squamous cell carcinoma cell lines. (2014)
  • Author(s): ２５．Ui T, Morishima K, Saito S, Sakuma Y, Fujii H, Hosoya Y, Yasuda Y, Niki T.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Remarks] 自治医科大学病理学講座統合病理学部門ホームページ
  • URL: https://www.jichi.ac.jp/pathol/index.html
• [Remarks] 自治医科大学統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/
• [Remarks] 自治医科大学病理学講座統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/