Breast cancer microenvironment control targeting clock gene and its clinical application

• Project/Area Number: 16K10448
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Hirosaki University
• Principal Investigator: Morohashi Satoko 弘前大学, 医学研究科, 助教 (90569592)
• Co-Investigator(Kenkyū-buntansha): 呉 雲燕 弘前大学, 医学研究科, 助教 (40636586) ; 鬼島 宏 弘前大学, 医学研究科, 教授 (90204859)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 時計遺伝子 / 微小環境 / ヒト癌細胞 / 乳癌 / ＴＧＦβ / 転写因子 / 分子標的治療薬

Outline of Final Research Achievements

Podoplanin is significantly associated with EMT of human cancer cells, and may be directly or indirectly regulated by bHLH transcription factors DEC1 and DEC2. DEC2 exhibits anti-apoptotic effects in human cancer cells. Reversal of DEC2 expression may have therapeutic potentials for the treatment of esophageal cancer, in combination with cisplatin. DEC1 and DEC2 have opposite effects on TGFβinduced EMT in human cancer cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、概日リズムの下で、時計遺伝子の発現に対応した癌細胞増殖・癌細胞－間質の相互作用・腫瘍血管新生の機序を証明することで、癌微小環境の病態解明と、増殖制御機構の構築を目標とすた。さらには、概日リズムおよび微小環境を考慮した新たな時計遺伝子をターゲットとした抗がん剤（分子標的治療薬を含む）の概念を構築することに挑んだ。時計遺伝子が、ヒト癌細胞において、アポトーシスや上皮間葉転換（EMT）に関与していることを示すことができた。このことは、時計遺伝子（DEC）が抗がん剤（分子標的治療薬）としての可能性を有していることと理解される。

Research Products

• [Journal Article] Gastric Focal Neutrophil Infiltration and Wide Duodenal Gastric Foveolar Metaplasia Are Histologic Discriminative Markers for Crohn’s Disease and Behcet’s Disease (2018)
  • Author(s): Akemoto Yui、Sakuraba Hirotake、Tanaka Masanori、Hiraga Hiroto、Kikuchi Hidezumi、Morohashi Satoko、Ota Shinji、Hasui Keisuke、Satake Miwa、Watanabe Rina、Tanaka Nahoko、Kawaguchi Shogo、Tatsuta Tetsuya、Sawaya Manabu、Chinda Daisuke、Mikami Tatsuya、Ishiguro Yoh、Kijima Hiroshi、Fukuda Shinsaku
  • Journal Title: Digestion Volume: 12 Issue: 3 Pages: 1-10
  • DOI: 10.1159/000494922
  • Peer Reviewed / Open Access
• [Journal Article] Neoangiogenesis of gastric submucosa-invasive adenocarcinoma (2018)
  • Author(s): Sasaki Hanae、Morohashi Satoko、Toba Takahito、Seino Hiroko、Yoshizawa Tadashi、Hirai Hideaki、Haga Toshihiro、Wu Yunyan、Kijima Hiroshi
  • Journal Title: Oncology Letters Volume: 3 Pages: 3895-3900
  • DOI: 10.3892/ol.2018.9116
  • Peer Reviewed / Open Access
• [Journal Article] Correlation between DEC1/DEC2 and epithelial-mesenchymal transition in human prostate cancer PC-3 cells (2018)
  • Author(s): Liu Qiang、Wu Yunyan、Seino Hiroko、Haga Toshihiro、Yoshizawa Tadashi、Morohashi Satoko、Kijima Hiroshi
  • Journal Title: Molecular Medicine Reports Volume: 4 Pages: 3859-3865
  • DOI: 10.3892/mmr.2018.9367
  • Peer Reviewed / Open Access
• [Journal Article] Intraoperative adjunctive mitomycin C and cryotherapy for recurrent conjunctival papillary sebaceous carcinoma (2018)
  • Author(s): Monai N, Tanabu R, Gonome T, Yokoi K, Urushidate S, Morohashi S, Hirai H, Kurose A, Nakazawa M
  • Journal Title: Case Reports in Ophthalmology Volume: 9 Issue: 1 Pages: 221-226
  • DOI: 10.1159/000487704
  • Peer Reviewed / Open Access
• [Journal Article] Expression of cancer-associated fibroblast markers in advanced colorectal cancer (2018)
  • Author(s): Nishishita Rie、Morohashi Satoko、Seino Hiroko、Wu Yunyan、Yoshizawa Tadashi、Haga Toshihiro、Saito Kensuke、Hakamada Kenichi、Fukuda Shinsaku、Kijima Hiroshi
  • Journal Title: Oncol Lett. Volume: 15 Pages: 6195-6202
  • DOI: 10.3892/ol.2018.8097
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the histological phenotype of extrahepatic bile duct carcinoma (2017)
  • Author(s): Okano Kensuke、Yoshizawa Tadashi、Miura Takuya、Ishido Keinosuke、Kudo Daisuke、Kimura Norihisa、Wakiya Taichi、Wu Yunyan、Morohashi Satoko、Hakamada Kenichi、Kijima Hiroshi
  • Journal Title: Mol Clin Oncol. Volume: 8 Pages: 54-60
  • DOI: 10.3892/mco.2017.1472
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Impact of Extracapsular Lymph Node Invasion and Myofibroblastic Activity in Extrahepatic Bile Duct Cancer (2017)
  • Author(s): Yoshizawa Tadashi、Ishido Keinosuke、Saito Kensuke、Haga Toshihiro、Seino Hiroko、Wu Yunyan、Morohashi Satoko、Hakamada Kenichi、Kijima Hiroshi
  • Journal Title: Clin Med Insights Pathol. Volume: 10 Pages: 1-7
  • DOI: 10.1177/1179555717729652
  • NAID: 120006583346
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Hyperparathyroidism due to a Large Intrathyroid Parathyroid Adenoma with Recurrent Episodes of Acute Pancreatitis (2017)
  • Author(s): Kageyama Kazunori、Ishigame Noriko、Sugiyama Aya、Igawa Akiko、Nishi Takashi、Morohashi Satoko、Kijima Hiroshi、Daimon Makoto
  • Journal Title: Case Rep Endocrinol. Volume: 2017 Pages: 1-5
  • DOI: 10.1155/2017/5376741
  • NAID: 120006576904
  • Peer Reviewed / Open Access
• [Journal Article] Contrast media enhancement reduction predicts tumor response to presurgical molecular-targeting therapy in patients with advanced renal cell carcinoma (2017)
  • Author(s): Hosogoe Shogo、Hatakeyama Shingo、Kusaka Ayumu、Hamano Itsuto、Tanaka Yoshimi、Hagiwara Kazuhisa、Hirai Hideaki、Morohashi Satoko、Kijima Hiroshi、Yamamoto Hayato、Tobisawa Yuki、Yoneyama Tohru、Yoneyama Takahiro、Hashimoto Yasuhiro、Koie Takuya、Ohyama Chikara
  • Journal Title: Oncotarget. Volume: 8 Issue: 30 Pages: 49749-49756
  • DOI: 10.18632/oncotarget.17930
  • NAID: 120006583348
  • Peer Reviewed / Open Access
• [Journal Article] DEC2 expression antagonizes cisplatin-induced apoptosis in human esophageal squamous cell carcinoma (2017)
  • Author(s): Sato Hidenobu、Wu Yunyan、Kato Yukio、Liu Qiang、Hirai Hideaki、Yoshizawa Tadashi、Morohashi Satoko、Watanabe Jun、Kijima Hiroshi
  • Journal Title: Mol Med Rep. Volume: 16 Issue: 1 Pages: 43-48
  • DOI: 10.3892/mmr.2017.6571
  • Peer Reviewed / Open Access
• [Journal Article] Neuropathology of PARK14 is identical to idiopathic Parkinson's disease (2017)
  • Author(s): Miki Y, Yoshizawa T, Morohashi S, Seino Y, Kijima H, Shoji M, Mori A, Yamashita C, Hatano T, Hattori N, Wakabayashi K
  • Journal Title: Mov Disord Volume: - Issue: 5 Pages: 35-35
  • DOI: 10.1002/mds.26952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Impact of CD163+ Macrophages in Tumor Stroma and CD8+ T-Cells in Cancer Cell Nests in Invasive Extrahepatic Bile Duct Cancer. (2017)
  • Author(s): Miura T, Yoshizawa T, Hirai H, Seino H, Morohashi S, Wu Y, Wakiya T, Kimura N, Kudo D, Ishido K, Toyoki Y, Kijima H, Hakamada K.
  • Journal Title: Anticancer Res Volume: 37 Issue: 1 Pages: 183-190
  • DOI: 10.21873/anticanres.11304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Podoplanin-mediated TGF-β-induced epithelial-mesenchymal transition and its correlation with bHLH transcription factor DEC in TE-11 cells. (2016)
  • Author(s): Wu Y, Liu Q, Yan X, Kato Y, Tanaka M, Inokuchi S, Yoshizawa T, Morohashi S, Kijima H.
  • Journal Title: Int J Oncol. Volume: 48 Issue: 6 Pages: 2310-2320
  • DOI: 10.3892/ijo.2016.3445
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Basic helix-loop-helix transcription factor DEC2 functions as an anti-apoptotic factor during paclitaxel-induced apoptosis in human prostate cancer cells. (2016)
  • Author(s): Liu Q, Wu Y, Yoshizawa T, Yan X, Morohashi S, Seino H, Kato Y, Kijima H.
  • Journal Title: Int J Mol Med Volume: 38 Issue: 6 Pages: 1727-1733
  • DOI: 10.3892/ijmm.2016.2798
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Myofibroblast distribution is associated with invasive growth types of colorectal cancer. (2016)
  • Author(s): Takatsuna M, Morohashi S, Yoshizawa T, Hirai H, Haga T, Ota R, Saito K, Wu Y, Seino H, Aoyagi Y, Terai S, Kijima H.
  • Journal Title: Oncol Rep Volume: 36 Issue: 6 Pages: 3154-3160
  • DOI: 10.3892/or.2016.5202
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Myofibroblasts of the muscle layer stimulate the malignant potential of colorectal cancer. (2016)
  • Author(s): Takatsuna M, Morohashi S, Yoshizawa T, Hirai H, Haga T, Ota R, Wu Y, Morohashi H, Hakamada K, Terai S, Kijima H.
  • Journal Title: Oncol Rep Volume: 36 Issue: 3 Pages: 1251-1257
  • DOI: 10.3892/or.2016.4932
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A new histological therapeutic classification system to predict eradicated and residual lymph nodes in breast cancer after neoadjuvant chemotherapy. (2016)
  • Author(s): Morohashi S, Yoshizawa T, Seino H, Hirai H, Haga T, Ota R, Wu Y, Yoshida E, Hakamada K, Kijima H.
  • Journal Title: Oncol Rep. Volume: 35 Issue: 5 Pages: 3592-3598
  • DOI: 10.3892/or.2016.4635
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] <b>Clinicopathological significance of gastric poorly differentiated medullary car</b><b>cinoma </b> (2016)
  • Author(s): Hirai H, Yoshizawa T, Morohashi S, Haga T, Wu Y, Ota R, Takatsuna M, Akasaka H, Hakamada K, Kijima H.
  • Journal Title: Biomedical Research Volume: 37 Issue: 2 Pages: 77-84
  • DOI: 10.2220/biomedres.37.77
  • NAID: 130005147429
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinicopathological significance of vascular endothelial growth factor, thymidine phosphorylase and microvessel density in colorectal cancer. (2016)
  • Author(s): 5.Kimura Y, Morohashi S, Yoshizawa T, Suzuki T, Morohashi H, Sakamoto Y, Koyama M, Murata A, Kijima H, Hakamada K.
  • Journal Title: Mol Med Rep. Volume: 13 Issue: 2 Pages: 1551-1557
  • DOI: 10.3892/mmr.2015.4687
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 乳腺疾患の現状について (2019)
  • Author(s): 諸橋聡子
  • Organizer: 青森県臨床細胞学会 教育講演
  • Invited
• [Presentation] 集塊エッジ・フラクタル解析法を用いた乳腺HCGの集塊不整性の評価 (2018)
  • Author(s): 吉岡 治彦, 下田 翼, 及川 颯大, 石山 雅大, 長谷川 善枝, 諸橋 聡子, 田中 正則, 堀江 香代, 渡邉 純
  • Organizer: 日本臨床細胞学会雑誌
• [Presentation] 潰瘍性大腸炎術後の残存直腸粘膜12例の解析(Morphological analysis of the residual rectal mucosa in 12 postoperative ulcerative colitis patients) (2017)
  • Author(s): 諸橋 聡子, 田中 正則, 吉澤 忠司, 清野 浩子, 呉 雲燕, 鬼島 宏
  • Organizer: 日本病理学会
• [Presentation] Utility of residual carcinoma pattern in breast cancer after neoadjuvant chemotherapy (2016)
  • Author(s): Satoko Morohashi, Tadashi Yoshizawa, Hiroko Seino,
  • 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