A project intended for new diagnostic marker and therapy for mesothelioma based on ubiquitin-proteasome system

• Project/Area Number: 18K06980
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Asahikawa Medical College
• Principal Investigator: Tanino Mishie 旭川医科大学, 医学部, 教授 (90360908)
• Co-Investigator(Kenkyū-buntansha): 北村 秀光 北海道大学, 遺伝子病制御研究所, 准教授 (40360531) ; 榊原 純 (小西純) 北海道大学, 大学病院, 講師 (50374278) ; 畠山 鎮次 北海道大学, 医学研究院, 教授 (70294973)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 悪性中皮腫 / 脱ユビキチン化酵素 / OTUB1 / 悪性胸膜中皮腫 / OTUB-1 / 上皮間葉移行 / 中皮腫 / ユビキチン

Outline of Final Research Achievements

Malignant mesothelioma(MM) is an aggressive tumor which originates from the mesothelial cells of the serosal tissues. It has been reported to be associated with inhalation exposure to asbestos. MM caused by asbestos exposure, and it will become tumor after 30 to 40 years latency period. MM is treated by multidisciplinary treatment combined with surgical excision, chemotherapy and radiation, but it shows treatment resistance and poor prognosis. A novel treatment method has been desired. In this study, we focused on the role of OTUB1, one of the deubiquitinating enzyme. OTUB1 was highly expressed in MM tissue and cell lines. It regulated TGF-beta/SMAD pathway, followed by their motility and invasion. These findings suggest OTUB1 is one of the candidate protein for new therapy of MM.

Academic Significance and Societal Importance of the Research Achievements

悪性中皮腫はアスベスト曝露後長い期間を経て発症する予後不良の疾患である。集学的治療に対しても抵抗性であり、新規治療法の開発が切望される。本研究では「ユビキチン-プロテアソーム系によるタンパク質制御」に着目し、悪性中皮腫における脱ユビキチン化酵素の一つであるOTUB1の役割に着目した。OTUB1は中皮腫細胞株やヒト悪性中皮腫組織で高発現しており、その過剰発現、ノックアウト細胞株を用いた研究で、TGF-beta/SMAD シグナル経路を介した悪性化に関与していることが明らかになった。中皮腫においてOTUB1が悪性化に寄与し、新規治療法のターゲットになりえる可能性が示唆された。

Research Products

• [Journal Article] Novel rapid immunohistochemistry using an alternating current electric field identifies Rac and Cdc42 activation in human colon cancer FFPE tissues (2022)
  • Author(s): Tsuda M, Horio R, Wang L, Takenami T, Moriya J, Suzuka J, Sugino H, Tanei Z, Tanino M, Tanaka S.
  • Journal Title: Sci Rep. Volume: 12 Issue: 1 Pages: 1733-1733
  • DOI: 10.1038/s41598-022-05892-7
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of BMP and Wnt Signals Leadingto Epithelial-Mesenchymal Transition in Colon Adenocarcinoma with Heterotopic Ossification. (2021)
  • Author(s): Katono N, Tsuda M, Suzuka J, Oda Y, Wang L, Tanei ZI, Tanino M, Ohata T, Nagabuchi E, Ishida Y, Kimura S, Iwanaga T, Tanaka S
  • Journal Title: Ann Clin Lab Sci Volume: 51 Pages: 271-276
  • Peer Reviewed / Open Access
• [Journal Article] The CD44/COL17A1 Pathway Plays a Vital Role in the Formation of Multilayered, Transformed Epithelia. (2021)
  • Author(s): Kozawa K, ,Sekai M, Ohba K, Ito S, Sako H, Maruyama T, Kakeno M , Kuromiya K, Kamasaki T, Kohashi K, Ishikawa S, Sato N, Asano S, Suzuki H, Tanimura N, Mukai Y, Gotoh N, Tanino M, Tanaka S Natsuga K, Soga T. Nakamura T, Yabuta Y, Saitou M, Ito T, Matsuura K, Tsunoda M,et.al..
  • Journal Title: Curr Biol Volume: 31 Issue: 14 Pages: 3086-3097
  • DOI: 10.1016/j.cub.2021.04.078
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological characteristics of Epstein-Barr virus and microsatellite instability subtypes of early gastric neoplasms classified by the Japanese and the World Health Organization criteria. (2021)
  • Author(s): Tanabe Hiroki、Mizukami Yusuke、Takei Hidehiro、Tamamura Nobue、Omura Yuhi、Kobayashi Yu、Murakami Yuki、Kunogi Takehito、Sasaki Takahiro、Takahashi Keitaro、Ando Katsuyoshi、Ueno Nobuhiro、Kashima Shin、Yuzawa Sayaka、Hasegawa Kimiharu、Sumi Yasuo、Tanino Mishie、Fujiya Mikihiro、Okumura Toshikatsu
  • Journal Title: The Journal of Pathology: Clinical Research Volume: - Issue: 4 Pages: 397-409
  • DOI: 10.1002/cjp2.209
  • Peer Reviewed / Open Access
• [Journal Article] A case of insulinoma diagnosed postpartum with hypoglycemia symptoms that were masked during pregnancy. (2021)
  • Author(s): Tomoe Abe, Yasutaka Takeda, Takao Takiyama, Ayaka Sasaki, Ryoichi Bessho, Mao Sato, Hiroya Kitsunai, Hidemitsu Sakagami, Atsuko Aiko, Koji Imai, Sayaka Yuzawa, Mishie Tanino, Yumi Takiyama.
  • Journal Title: Clin Case Rep Volume: 9 Issue: 4 Pages: 1-8
  • DOI: 10.1002/ccr3.3924
  • Peer Reviewed / Open Access
• [Journal Article] Spontaneous pneumothorax caused by an inflammatory myofibroblastic tumor-like lesion in a 14-year-old girl: a case report. (2020)
  • Author(s): Miyagi H, Ishii D, Hirasawa M, Yasuda S, Toriumi N, Sarashina T, Tanino M, Tanaka M, Tanaka Y, Miyamoto K.
  • Journal Title: Surg Case Rep Volume: 6 Issue: 1 Pages: 109-109
  • DOI: 10.1186/s40792-020-00873-2
  • Peer Reviewed / Open Access
• [Journal Article] Pleural sarcomatoid mesothelioma with an interstitial growth pattern. (2020)
  • Author(s): Miyakawa K, Yamamoto M, Akiyama N, Sado M, Yuzawa S, Okizaki A, Nishikawa Y, Takei H, Tanino M.
  • Journal Title: Pathol Int Volume: 70 Issue: 2 Pages: 126-128
  • DOI: 10.1111/pin.12890
  • Peer Reviewed
• [Journal Article] A 47-Year-Old Woman with Pulmonary Nodules and Facial Hemispasms (2020)
  • Author(s): Noriko H, Kensuke O, Mishie T, Yoshinobu O.
  • Journal Title: CHEST Volume: 158 Issue: 4 Pages: e197-e204
  • DOI: 10.1016/j.chest.2020.03.078
  • Peer Reviewed / Open Access
• [Journal Article] Resection for pancreatic cancer metastases contributes to survival: A case report with sequential tumor genotype profiling during the long-term postoperative course (2020)
  • Author(s): Sato H, Sasajima J, Okada T, Hayashi A, Kawabata H, Goto T, Koizumi K, Tamamura N, Tanabe H, Fujiya M, Chiba S, Tanino M, Ono Y, Mizukami Y, Okumura T.
  • Journal Title: Medicine (Baltimore) Volume: 99 Issue: 25 Pages: e20564-e20564
  • DOI: 10.1097/md.0000000000020564
  • Peer Reviewed / Open Access
• [Journal Article] Imaging and pathological evaluation of deep intramural ventricular tachycardia after combined bipolar and ethanol ablation (2020)
  • Author(s): Sakamoto N, Komatsu Y, Otsu K, Kamikokura Y, Hontani M, Sugiyama E, Minoshima A, Tanabe Y, Sekiguchi Y, Tanino M, Sato N, Kawamura Y, Nogami A, Aonuma K, Hasebe N.
  • Journal Title: JACC Clin Electrophysiol Volume: 6 Issue: 14 Pages: 1865-1866
  • DOI: 10.1016/j.jacep.2020.08.040
  • Peer Reviewed
• [Presentation] アスベスト曝露が示唆される偽中皮腫肺癌の剖検症例 (2021)
  • Author(s): 田中真奈実、遠藤哲史、秋葉裕二、上小倉佑機、湯澤明夏、佐藤啓介、谷野美智枝
  • Organizer: 第110回日本病理学会総会
• [Presentation] アスベスト曝露が示唆される偽中皮腫性肺癌の剖検症例. (2021)
  • Author(s): 田中真奈実, 遠藤哲史, 秋葉裕二, 上小倉佑機, 湯澤明夏, 佐藤啓介, 谷野美智枝
  • Organizer: 第110回日本病理学会総会
• [Presentation] Interstitial growth patternの肺内進展をきたした肉腫型悪性胸膜中皮腫の1例. (2020)
  • Author(s): 宮川京大, 山本雅大, 佐々木高明, 大崎能伸, 湯澤明夏, 武井英博, 谷野美智枝
  • Organizer: 第119回日本呼吸器学会北海道地方会
• [Presentation] The role of OTUB1 in human malignant mesothelioma (2018)
  • Author(s): 谷野美智枝
  • Organizer: 第107回日本病理学会総会
• [Book] 縦隔腫瘍・胸膜腫瘍 腫瘍病理鑑別診断アトラス第二版 (2022)
  • Author(s): 谷野美智枝 他
  • Total Pages: 325
  • Publisher: 文光堂
• [Book] 非腫瘍性疾患病理アトラス 肺 (2022)
  • Author(s): 谷野美智枝 他
  • Total Pages: 437
  • Publisher: 文光堂
• [Remarks] 旭川医科大学病院 病理部
  • URL: https://asahikawa-patho.net/
• [Patent(Industrial Property Rights)] 固定生体組織内での活性型低分子量GTP結合蛋白質検出方法 (2020)
  • Inventor(s): 田中伸哉、津田真寿実、谷野美智枝
  • Industrial Property Rights Holder: 田中伸哉、津田真寿実、谷野美智枝
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Acquisition Date: 2020