Molecular dissection of angiogenesis in colorectal cancer

• Project/Area Number: 18K07949
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Yamamoto Eiichiro 札幌医科大学, 医学部, 訪問研究員 (60567915)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 大腸がん / 微小環境 / がん微小環境 / 腫瘍血管 / がん間質 / 遺伝子発現

Outline of Final Research Achievements

We detected frequent upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in TECs. Immunohistochemistry revealed that AEBP1 is upregulated TECs and cancer stromal cells. Levels of AEBP1 expression in human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct co-culture with CRC cells. AEBP1 knockdown suppressed proliferation, migration and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 may promote angiogenesis through regulating those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

腫瘍間質は、がん関連線維芽細胞、腫瘍血管内皮細胞(tumor endothelial cell, TEC)、種々の免疫細胞などから構成されている。腫瘍間質細胞はがんの増殖、浸潤および転移に有利な微小環境を構築することから、その制御は重要な治療戦略である。本研究でAEBP1 (adipocyte enhancer-binding protein 1) がTECで高発現し、血管新生を促進すること、そしてAEBP1の阻害が腫瘍血管新生を抑制しうることを明らかとしており、今後がん微小環境におけるAEBP1の機能を解明することで、新たな分子標的治療法の開発につなげることができると考えられた。

Research Products

• [Journal Article] The continuum of transformation of TSA to low‐grade neoplasia and cancer with BRAF mutation ? A case with molecular analysis (2021)
  • Author(s): Aoki Hironori、Adachi Yasushi、Yamamoto Eiichiro、Yoshida Yukinari、Ishii Yoshifumi、Yamano Hiro‐o、Suzuki Hiromu、Endo Takao
  • Journal Title: Pathology International Volume: － Issue: 5 Pages: 368-370
  • DOI: 10.1111/pin.13078
  • Peer Reviewed
• [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] Significance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum (2020)
  • Author(s): Nakanishi, H. Sawada, T. Kaizaki, Y. Ota, R. Suzuki, H. Yamamoto, E. Aoki, H. Eizuka, M. Hasatani, K. Takahashi, N. Inagaki, S. Ebi, M. Kato, H. Kubota, E. Kataoka, H. Takahashi, S. Tokino, T. Minamoto, T. Sugai, T. Sasaki, Y.
  • Journal Title: PLoS One Volume: 15 Issue: 2 Pages: e0229262-e0229262
  • DOI: 10.1371/journal.pone.0229262
  • Peer Reviewed / Open Access
• [Journal Article] Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas (2020)
  • Author(s): Ota R、Sawada T、Tsuyama S、Sasaki Y、Suzuki H、Kaizaki Y、Hasatani K、Yamamoto E、Nakanishi H、Inagaki S、Tsuji S、Yoshida N、Doyama H、Minato H、Nakamura K、Kasashima S、Kubota E、Kataoka H、Tokino T、Yao T、Minamoto T
  • Journal Title: The Journal of Pathology Volume: 252 Issue: 3 Pages: 330-342
  • DOI: 10.1002/path.5529
  • Peer Reviewed / Open Access
• [Journal Article] Molecular biology of colorectal cancer -mechanism of tumorigenesis and molecular subtypes- (2019)
  • Author(s): 鈴木 拓、山本 英一郎、仲瀬 裕志
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 116 Issue: 11 Pages: 859-866
  • DOI: 10.11405/nisshoshi.116.859
  • NAID: 130007743552
  • ISSN: 0446-6586, 1349-7693
  • Year and Date: 2019-11-10
  • Peer Reviewed
• [Journal Article] Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13?months (2019)
  • Author(s): Amemori Sadahiro、Yamano Hiro‐o、Tanaka Yoshihito、Yoshikawa Kenjiro、Matsushita Hiro‐o、Takagi Ryo、Harada Eiji、Yoshida Yuko、Tsuda Kazunori、Kato Bunichiro、Tamura Eri、Eizuka Makoto、Sugai Tamotsu、Adachi Yasushi、Yamamoto Eiichiro、Suzuki Hiromu、Nakase Hiroshi
  • Journal Title: Digestive Endoscopy Volume: － Issue: 6 Pages: 979-983
  • DOI: 10.1111/den.13572
  • 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] Integrated Analysis of the Endoscopic, Pathological and Molecular Characteristics of Colorectal Tumorigenesis. (2019)
  • Author(s): Suzuki H, Yamamoto E, Yamano HO, Nakase H, Sugai T.
  • Journal Title: Digestion. Volume: 99 Issue: 1 Pages: 33-38
  • DOI: 10.1159/000494410
  • 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
• [Journal Article] Analysis of the expression of cancer-associated fibroblast- and EMT-related proteins in submucosal invasive colorectal cancer. (2018)
  • Author(s): Sugai T, Uesugi N, Kitada Y, Yamada N, Osakabe M, Eizuka M, Sugimoto R, Fujita Y, Kawasaki K, Yamamoto E, Yamano H, Suzuki H, Matsumoto T.
  • Journal Title: J Cancer. Volume: 9 Issue: 15 Pages: 2702-2712
  • DOI: 10.7150/jca.25646
  • 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] Molecular Profiling Based on KRAS/BRAF Mutation, Methylation, and Microsatellite Statuses in Serrated Lesions. (2018)
  • Author(s): Sugai T, Eizuka M, Fujita Y, Kawasaki K, Yamamoto E, Ishida K, Yamano H, Suzuki H, Matsumoto T.
  • Journal Title: Dig Dis Sci. Volume: 63 Issue: 10 Pages: 2626-2638
  • DOI: 10.1007/s10620-018-5167-4
  • Peer Reviewed / Open Access
• [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] Comprehensive molecular analysis based on somatic copy number alterations in intramucosal colorectal neoplasias and early invasive colorectal cancers. (2018)
  • Author(s): Sugai T, Eizuka M, Habano W, Fujita Y, Sato A, Sugimoto R, Otsuka K, Yamamoto E, Matsumoto T, Suzuki H.
  • Journal Title: Oncotarget. Volume: 9 Issue: 33 Pages: 22895-22906
  • DOI: 10.18632/oncotarget.25112
  • 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] Molecular profiling and comprehensive genome-wide analysis of somatic copy number alterations in gastric intramucosal neoplasias based on microsatellite status. (2018)
  • Author(s): Sugai T, Eizuka M, Arakawa N, Osakabe M, Habano W, Fujita Y, Yamamoto E, Yamano H, Endoh M, Matsumoto T, Suzuki H.
  • Journal Title: Gastric Cancer. Volume: 21 Issue: 5 Pages: 765-775
  • DOI: 10.1007/s10120-018-0810-5
  • NAID: 40021642313
  • Peer Reviewed / Open Access
• [Patent(Industrial Property Rights)] がん微小環境を制御する治療剤 (2018)
  • Inventor(s): 山本 英一郎、鈴木 拓、萬 顕、菅井 有
  • Industrial Property Rights Holder: 山本 英一郎、鈴木 拓、萬 顕、菅井 有
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-146981
  • Filing Date: 2018