Study on a novel mechanism of gemcitabine resistance

2018 Fiscal Year Annual Research Report

• Project/Area Number: 17K15648
• Research Institution: Nara Medical University
• Principal Investigator: 谷 里奈 奈良県立医科大学, 医学部, 助教 (20783872)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: MAST4 / AKT3 / ゲムシタビン / 膵管癌

Outline of Annual Research Achievements

膵管癌に対する化学療法は、使用される抗がん剤への耐性により適応には限界がある。膵管癌の抗癌剤耐性への治療法を確立するため、われわれは、gemcitabine(GEM)に対する耐性機序について検討を行った。ヒト膵管癌細胞株MIA-PaCa-2(MIA-P)に低濃度でGEMを持続処理することで、GEM耐性の細胞株MIA-Gを樹立した。MIA-GのGEMに対するIC50は、MIA-Pと比較し約1000倍の差が認められた。MIA-PとMIA-G間で遺伝子プロファイルを比較すると、Microtubule-associated serine/threonine kinase 4(MAST4)の発現は約6倍亢進しており、MAST4のノックダウンによりMIA-GのGEM耐性はMIA-Pと同程度まで低下した。膵管癌臨床検体91症例を用いた免疫染色では、MAST4は正常膵管上皮では細胞質に、膵管癌細胞では細胞質と核に発現しており、核への染色性は予後と逆相関を示していた。MIA-Gにおいて、MIA-Pに比較し細胞質・核ともにMAST4タンパクレベルの亢進が認められた。このように、核内MAST4がGEM耐性機序に関与することが示唆された。

Research Products

• [Int'l Joint Research] 南通大学(中国)
  • Country Name: CHINA
  • Counterpart Institution: 南通大学
• [Journal Article] Targeting claudin-4 enhances CDDP-chemosensitivity of gastric cancer (2019)
  • Author(s): Nishiguchi Y, Fujiwara-Tani R, Sasaki T, Luo Y, Ohmori H, Kishi S, Mori S, Goto K, Yasui W, Sho M, Kuniyasu H
  • Journal Title: Oncotarget 10 (22): 2189-2202; 2019. Volume: 10 Pages: 2189-2202
  • DOI: 10.18632/oncotarget.26758
  • Open Access / Int'l Joint Research
• [Journal Article] Concurrent expression of CD47 and CD44 in colorectal cancer promotes malignancy (2019)
  • Author(s): Fujiwara-Tani R, Sasaki T, Ohmori H, Luo Y, Goto K, Nishiguchi Y, Mori S, Nakashima C, Mori T, Miyagawa Y, Kawahara I, Fujii K, Kishi S, Tatsumoto N, Kuniyasu H
  • Journal Title: Pathobiology Volume: in press Pages: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Magnetic hyperthermia using self-controlled heating elements consisting of Fe-Al milling alloy induces cancer cell apoptosis while preserving skeletal muscle. (2019)
  • Author(s): Kawahara I, Goto K, Kodama K, Luo Y, Fujiwara-Tani R, Mori T, Miyagawa Y, Tanaka H, Kodama H, Hirayama A, Hosoito N, Taniguchi Y, Miki Y, Kuniyasu H
  • Journal Title: Pathobiology Volume: in press Pages: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intermittent calorie restriction enhances epithelial-mesenchymal transition through alteration of energy metabolism in a mouse tumor model. (2018)
  • Author(s): Kusuoka O, Fujiwara-Tani R, Nakashima C, Fujii K, Ohmori H, Mori T, Kishi S, Miyagawa Y, Goto K, Kawahara I, Kuniyasu H
  • Journal Title: Int J Oncol 52 Volume: 52 Pages: 413-423
  • DOI: 10.3892/ijo.2017.4229
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of cytosolic malic enzyme (ME1) is associated with disease progression in human oral squamous cell carcinoma. (2018)
  • Author(s): Nakashima C, Yamamoto K, Fujiwara-Tani R, Luo Y, Matsushima S, Fujii K, Ohmori H, Sasahira T, Sasaki T, Kitadai Y, Kirita T, Kuniyasu H
  • Journal Title: Cancer Sci Volume: 109 Pages: 2036-2045
  • DOI: 10.1111/cas.13594
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pro-metastatic signaling of elaidic acid, a trans fatty acid, is associated with lipid rafts. (2018)
  • Author(s): Kishi S, Fujiwara-Tani R, Luo Y, Kawahara I, Goto K, Fujii K, Ohmori H, Nakashima C, Sasaki T, Kuniyasu H
  • Journal Title: Oncol Lett Volume: 15 Pages: 4423-4426
  • DOI: 10.3892/ol.2018.7817
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of the long-chain fatty acid receptor GPR40 was associated with cancer progression in colorectal cancer. (2018)
  • Author(s): Nakashima C, Kishi S, Fujiwara-Tani R, Luo Y, Kawahara I, Goto K, Fujii K, Ohmori H, Kuniyasu H
  • Journal Title: Oncol Lett 15(6): , 2018 Volume: 15 Pages: 8641-8646
  • DOI: 10.3892/ol.2018.8383
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of intranuclear angiotensin-II type 2 receptor in oral squamous cell carcinoma (2018)
  • Author(s): Matsushima-Otsuka S, Fujiwara-Tani R, Sasaki T, Ohmori H Nakashima C, Kishi S, Nishiguchi Y, Fujii K, Luo Y, Kuniyasu H
  • Journal Title: Oncotarget 9(93): , 2018 Volume: 9 Pages: 36561-36574
  • DOI: org/10.18632/oncotarget.26337
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intake of medium-chain fatty acids induces oxidative stress and to atrophy the myocardium (2018)
  • Author(s): Miyagawa Y, Mori T, Goto K, Fujiwara-Tani R, Kishi S, Sasaki T, Fujii K, Ohmori H, Kawahara I, Kuniyasu H
  • Journal Title: Lipids in Health and Disease Volume: 17 Pages: 258
  • DOI: org/10.1186/s12944-018-0908-0
  • Peer Reviewed / Open Access
• [Journal Article] Anti-claudin-4 extracellular domain antibody enhances the antitumoral effects of chemotherapeutic and antibody drugs in colorectal cancer (2018)
  • Author(s): Fujiwara-Tani R, Sasaki T, Luo Y, Ohmori H, Nishiguchi Y, Kishi S, Mori S, Goto K, Kondoh M, Kuniyasu H
  • Journal Title: Oncotarget 9(100):, 2018 Volume: 9 Pages: 37367-37378
  • DOI: 10.18632/oncotarget.26427
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 膵管癌細胞株MIA-PaCa-2のgemcitabine耐性獲得におけるミトコンドリア代謝変化の検討 (2019)
  • Author(s): 谷 里奈、森 汐莉、佐々木隆光、岸 真五、國安弘基
  • Organizer: 第108回日本病理学会総会、東京都、2019.5.9-11
• [Presentation] 膵管癌のgemcitabine耐性獲得におけるMAST4の役割 (2018)
  • Author(s): 谷 里奈、森 汐莉、佐々木隆光、岸 真五、國安弘基
  • Organizer: 第107回日本病理学会総会、札幌市、2018.6.21-23
• [Presentation] MAST4 expression correlates with gemcitabine resistance in pancreatic ductal carcinoma. (2018)
  • Author(s): Fujiwara-Tani R, Kishi S, Mori S, Sasaki T, Kuniyasu H
  • Organizer: 77th Annual Meeting of Japanese Association for Cancer, Osaka, 2018.9.28-30
• [Remarks] 奈良県立医科大学分子病理学HP
  • URL: http://www.naramed-u.ac.jp/~molepath/