Hippo signaling pathway regulates proliferation and ECM production in cancer cells

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592788
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: FUJII Makiko 愛知県がんセンター(研究所), 分子腫瘍学部, 主任研究員 (70406031)
• Project Period (FY): 2011 – 2013
• Keywords: YAP / TGF-β / Hippo signal / CTGF

Research Abstract

Hippo signaling pathway inhibits the transcriptional coactivation activity of Yes-associated protein (YAP) by inducing phosphorylation and cytoplasmic retention of YAP. In this study, we have found a functional interaction between the Hippo and TGF-beta pathways in regulating connective tissue growth factor (CTGF). Expression of CTGF in malignant tumor cells was induced by the formation of a YAP/TEAD4/Smad3/p300 complex on the CTGF promoter. Our data suggest that CTGF is an important modulator of tumor cell growth.

Research Products

• [Journal Article] RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer (2014)
  • Author(s): Fukatsu A, Ishiguro F, Tanaka I, Kudo T, Nakagawa K, Shinjo K, Kondo Y, Fujii M, Hasegawa Y, Tomizawa T, Mitsudomi T, Osada H, Hata Y, Sekido Y
  • Journal Title: Lung Cancer Volume: 83 Pages: 23-9
• [Journal Article] Smad7-Skp2 complex orchestrates c-Myc stability, impacting on the cytostatic effect of TGF-β (2013)
  • Author(s): Kim TA, Kang JM, Hyun JS, Lee B, Kim SJ, Yang ES, Hong S, Lee HJ, Fujii M, Niederhuber JE, Kim SJ
  • Journal Title: J Cell Sci Volume: 82 Pages: 24-30
• [Journal Article] A LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade (2013)
  • Author(s): Tanaka I, Osada H, Fujii M, Fukatsu A, Hida T, Horio Y, Kondo Y, Sato A, Hasegawa Y, Tsujimura T, Sekido Y
  • Journal Title: Oncogene 2013 Volume: (accepted)
• [Journal Article] High expression of SNIP1 correlates with poor prognosis in non-small cell lung cancer and SNIP1 interferes with the recruitment of HDAC1 to RB: in vitro. (2013)
  • Author(s): Jeon HS, Choi YY, Fukuoka J, Fujii M, Lyakh LA, Song SH, Travis WD, Park JY, Jen J
  • Journal Title: Lung Cancer Volume: 82 Pages: 24-30
• [Journal Article] Hepatitis Virus Infection Affects DNA Methylation in Mice with Humanized Livers (2013)
  • Author(s): Okamoto Y, Shinjo k, Shimizu Y, Sano T, Yamao K, Gao W, Fujii M, Osada H, Sekido Y, Murakami S, Tanaka Y, Joh T, Sato S, Takahashi S, Wakita T, Zhu J, Issa JP, Kondo Y
  • Journal Title: Gastroenterology Volume: 146 Pages: 562-72
• [Journal Article] Membranous expression of activated leukocyte cell adhesion molecule contributes to poor prognosis and malignant phenotypes of non-small- cell lung cancer (2013)
  • Author(s): Ishiguro F, Murakami H, Mizuno T, Fujii M, Kondo Y, Usami N, Taniguchi T, Yokoi K, Osada H, Sekido Y
  • Journal Title: J Surg Res Volume: 179 Pages: 24-32
• [Journal Article] TGF-βsignaling and defects in the Hippo signaling cascade (2012)
  • Author(s): Fujii M, Nakanishi H, Toyoda T, Tanaka I, Kondo Y, Osada H, Sekido Y
  • Journal Title: Cell Cycle Volume: Extra-view 11 Pages: 1-7
• [Journal Article] Exploration of a new drug that targets YAP J Biochem (2012)
  • Author(s): Fujii M
  • Journal Title: Commentary Volume: 152 Pages: 209-11
• [Journal Article] Contribution of MicroRNA-1275 to Claudin11 Protein Suppression via a Polycomb-mediated Silencing Mechanism in Human Glioma Stem-like Cells (2012)
  • Author(s): Katsushima K, Shinjo K, Natsume A, Ohka F, Fujii M, Osada H, Sekido Y, Kondo Y
  • Journal Title: J Biol Chem Volume: 287 Pages: 27396-406
• [Journal Article] Activated Leukocyte Cell-Adhesion Molecule (ALCAM) Promotes Malignant Phenotypes of Malignant Mesothelioma (2012)
  • Author(s): Ishiguro F, Murakami H, Mizuno T, Fujii M, Kondo Y, Usami N, Yokoi K, Osada H, Sekido Y
  • Journal Title: J Thorac Oncol Volume: 7 Pages: 890-9
• [Journal Article] Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical character of lung adenocarcinoma (2012)
  • Author(s): Shinjo K, Okamoto Y, An B, Yokoyama T, Takeuchi I, Fujii M, Osada H, Usami N, Hasegawa Y, Ito H, Hida T, Fujimoto N, Kishimoto T, Sekido Y, Kondo Y
  • Journal Title: Carcinogenesis Volume: 33 Pages: 1277-85
• [Journal Article] TGF-βsynergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth (2012)
  • Author(s): Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Matsudaira Y, Ito H, Murakami H, Kondo Y, Kondo E, Hida T, Tsujimura T, Osada H, Sekido Y
  • Journal Title: J. Exp. Med Volume: 209 Pages: 479-94
• [Journal Article] Acquisition of EMT phenptype in the gefitinib-resistant cells of a head and neck squamous cell carcinoma cell line through Akt/GSK3β/snail signaling pathway (2012)
  • Author(s): Maseki S, Ijichi K, Tanaka H, Fujii M, Hasegawa Y, Ogawa T, Murakami S, Kondo E, Nakanishi H
  • Journal Title: Br. J. Cancer Volume: 106 Pages: 1196-204
• [Journal Article] Activated Leukocyte Cell Adhesion Molecule (ALCAM) Promotes Malignant Phenotypes of Malignant Mesothelioma (2012)
  • Author(s): Ishiguro F, Murakami H, Mizuno T, Fujii M, Kondo Y, Usami N, Yokoi K, Osada H, Sekido Y
  • Journal Title: J Thorac Oncol Volume: 7 Pages: 890-9
• [Journal Article] YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes (2012)
  • Author(s): Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, Akatsuka S, Toyokuni S, Yokoi K, Osada H, Sekido Y
  • Journal Title: Oncogene Volume: 31 Pages: 5117-22
• [Journal Article] Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumor (2012)
  • Author(s): Okamoto Y, Sawaki A, Ito S, Nishida T, Takahashi T, Toyota M, Suzuki H, Shinomura Y, Takeuchi I, Shinjo K, An B, Ito H, Yamao K, Fujii M, Murakami H, Osada H, Kataoka H, Joh T, Sekido Y, Kondo Y
  • Journal Title: Gut Volume: 61 Pages: 392-401
• [Journal Article] Regulation of endothelial barrier function by TGF-βtype I receptor ALK5: potential role of contractile mechanisms and heat shock protein 90 (2012)
  • Author(s): Antonov AS, Antonova GN, Fujii M, ten Dijke P, Handa V, Catravas JD, Verin AD
  • Journal Title: J Cell Physiol Volume: 227 Pages: 759-71
• [Journal Article] Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib (2011)
  • Author(s): Suda K, Tomizawa K, Fujii M, Murakami H, Osada H, Maehara Y, Yatabe Y, Sekido Y, Mitsudomi T
  • Journal Title: J Thorac Oncol Volume: 6 Pages: 1152-61
• [Journal Article] Distinct Profiles of Epigenetic Evolution between Colorectal Cancers with and without Metastasis (2011)
  • Author(s): Ju HX, An B, Okamoto Y, Shinjo K, Kanemitsu Y, Komori K, Hirai T, Shimizu Y, Sano T, Sawaki A, Tajika M, Yamao K, Fujii M, Murakami H, Osada H, Ito H, Takeuchi I, Sekido Y, Kondo Y
  • Journal Title: Am J Pathol Volume: 178 Pages: 1835-46
• [Journal Article] LATS2 is a tumor suppressor gene of malignant mesothelioma (2011)
  • Author(s): Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y
  • Journal Title: Cancer Res Volume: 71 Pages: 873-83
• [Presentation] Large intergenic non-coding RNA associated with stemness feature of glioma stem-like cell (2013)
  • Author(s): 勝島啓佑、新城恵子、大岡史治、藤井万紀子、長田啓隆、関戸好孝、夏目敦至、近藤豊
  • Organizer: 平成24年度「個体レベルでのがん研究支援活動」ワークショップ
  • Year and Date: 20130200
• [Presentation] 非上皮由来がん細胞におけるTGF-βによる腫瘍増殖促進作用 (2013)
  • Author(s): 藤井万紀子、田中一大、近藤豊、長田啓隆、関戸好孝
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-05
• [Presentation] 非小細胞肺癌におけるRASSF3の発現解析 (2013)
  • Author(s): 深津明日樹、田中一大、新城恵子、近藤豊、藤井万紀子、長谷川好規、富沢健二、光冨徹哉、長田啓隆、畑裕、関戸好孝
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-05
• [Presentation] LIMドメインを持つAJUBA蛋白質は、Hippoシグナル経路を介して悪性中皮腫細胞の増殖を抑制する (2013)
  • Author(s): 田中一大、長田啓隆、藤井万紀子、深津明日樹、樋田豊明、佐藤鮎子、長谷川好規、辻村亨、関戸好孝
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-05
• [Presentation] Convergent signaling in the regulatuion of malignant mesothelioma growth through CTGF : TGF-βsignaling and defects in the Hippo signaling pathway (2013)
  • Author(s): Fujii M, Nakanishi H, Toyoda T, Tanaka I, Kondo Y, Osada H, Sekido Y
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference
  • Place of Presentation: Hawaii
  • Year and Date: 2013-02-24
• [Presentation] A LIM-domain protein Ajuba suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade (2012)
  • Author(s): 田中一大、長田啓隆、藤井万紀子、関戸好孝
  • Organizer: Global COE第4回国際シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2012-11-15
• [Presentation] Convergent signaling in the regulatuion of malignant mesothelioma growth : TGF-βsignaling and defects in the Hippo signaling pathway (2012)
  • Author(s): Fujii M, Nakanishi H, Toyoda T, Tanaka I, Kondo Y, Osada H, Sekido Y
  • Organizer: 2nd JSPS International TGF-βSymposium
  • Place of Presentation: 東京
  • Year and Date: 2012-10-02
• [Presentation] 脳腫瘍幹細胞の分化に関わるlincRNAの網羅的解析及びその生化学的解析 (2012)
  • Author(s): 勝島啓佑、新城恵子、大岡史治、藤井万紀子、長田啓隆、関戸好孝、夏目敦至、柴田龍弘、近藤豊
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] 膠芽腫マウスモデルを用いたp53、Nf1欠失から引き起こされるエピジェネティクス異常の解析 (2012)
  • Author(s): 大岡史治、夏目敦至、若林俊彦、勝島啓佑、新城恵子、藤井万紀子、長田啓隆、関戸好孝、近藤豊
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] 悪性中皮腫におけるHippoシグナリングの欠失とTGF-βの協調によるCTGFの発現調節 (2012)
  • Author(s): 藤井万紀子、豊田武士、中西速夫、近藤豊、長田啓隆、関戸好孝
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] 悪性中皮腫細胞の増殖におけるConnective Tissue Growth Factor (CTGF)の役割について (2012)
  • Author(s): 藤井万紀子
  • Organizer: 第7回肺癌分子病態研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-09-15
• [Presentation] Hippo signaling pathway inactivation in malignant mesothelioma cells (2012)
  • Author(s): Sekido Y, Tanaka I, Osada H, Fujii M
  • Organizer: iMig (international Mesothelioma interest group)2012
  • Place of Presentation: Boston
  • Year and Date: 2012-09-13
• [Presentation] Contribution of microRNA-1275 to Claudin11 suppression via polycomb-mediated silencing mechanism in human glioma stem-like cells (2012)
  • Author(s): Katsushima K, Shinjo K, Natsume A, Ohka F, Fujii M, Osada H, Sekido Y, Kondo Y
  • Organizer: Sapporo Cancer Epigenetics Seminar of the A3 Foresight Program 2012
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-01
• [Presentation] Contribution of microRNA-1275 to Claudin11 suppression via polycomb-mediated silencing mechanism in human glioma stem-like cells (2012)
  • Author(s): 勝島啓佑、新城恵子、夏目敦至、大岡史治、藤井万紀子、長田啓隆、関戸好孝、近藤豊
  • Organizer: 第6回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-14
• [Presentation] TGF-βsynergizes with defects in the Hippo pathway by inducing CTGF expression (2012)
  • Author(s): Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Hida T, Tsujimura T, Osada H, Sekido Y
  • Organizer: American Association Cancer Research Annual Meeting 2012
  • Place of Presentation: Cicago
  • Year and Date: 2012-04-02
• [Presentation] Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma (2012)
  • Author(s): Shinjo K, Okamoto Y, Takeuchi I, Fujii M, Osada H, Usami N, Ito H, Hida T, Sekido Y, Kondo Y
  • Organizer: American Association Cancer Research Annual Meeting 2012
  • Place of Presentation: Cicago
  • Year and Date: 2012-04-02
• [Presentation] Epigenetic regulation of miR-1275 through histone H3 lysine 27 trimethylation during human glioma stem-like cell differentiation (2012)
  • Author(s): Katsushima K, Shinjo K, Ohka F, Fujii M, Osada H, Sekido Y, Natsume A, Kondo Y
  • Organizer: American Association Cancer Research Annual Meeting 2012
  • Place of Presentation: Cicago
  • Year and Date: 2012-04-02
• [Presentation] 悪性中皮腫細胞の増殖におけるTGF-βシグナルとhippo pathwayの役割 (2011)
  • Author(s): 藤井万紀子、豊田武士、中西速夫、谷田部恭、佐藤鮎子、村上秀樹、近藤豊、近藤栄作、樋田豊明、辻村亨、長田啓隆、関戸好孝
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] 肺腺癌の生物学的特性に関わるDNAメチル化異常の網羅的解析 (2011)
  • Author(s): 新城恵子、近藤豊、岡本泰幸、横山俊彦、宇佐美範泰、藤本伸一、岸本卓巳、樋田豊明、藤井万紀子、村上秀樹、長田啓隆、関戸好孝
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] 脳腫瘍幹細胞の分化に関わるmiR-1275に関する研究 (2011)
  • Author(s): 勝島啓佑、新城恵子、藤井万紀子、長田啓隆、関戸好孝、夏目敦至、近藤豊
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] ヒト悪性中皮腫細胞におけるYAP transcriptional coactivatorのCCND1を介した増殖機構の解析 (2011)
  • Author(s): 水野鉄也、村上秀樹、藤井万紀子、石黒太志、近藤豊、赤塚慎也、豊國伸哉、横井香平、長田啓隆、関戸好孝
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] 悪性中皮腫におけるALCAM/CD166発現の解析 (2011)
  • Author(s): 石黒太志、村上秀樹、水野鉄也、藤井万紀子、近藤豊、宇佐美範泰、横井香平、長田啓隆、関戸好孝
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] TGF-βsynergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth by inducing CTGF expression (2011)
  • Author(s): Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Matsudaira Y, Ito H, Murakami H, Kondo Y, Hida T, Tsujimura T, Osada H, Sekido Y
  • Organizer: Signaling in Development and Disease
  • Place of Presentation: イタリア
  • Year and Date: 2011-08-22
• [Presentation] 悪性中皮腫細胞の増殖におけるCTGF (connective tissue growth factor)の役割について (2011)
  • Author(s): 藤井万紀子、豊田武士、長田啓隆、谷田部恭、松平康枝、村上秀樹、近藤豊、樋田豊明、関戸好孝
  • Organizer: 日本組織培養学会第84回大会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-28