PP6 as a tumor suppressor in mouse two-stage chemical carcinogenesis

• Project/Area Number: 15K10081
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: KAKUGAWA Yoichiro 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん薬物療法研究部, 特任研究員 (60221173)
• Co-Investigator(Kenkyū-buntansha): 島 礼 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん薬物療法研究部, 部長 (10196462) ; 佐藤 郁郎 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), ティッシュバンクセンター, 部長 (50225918)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 紫外線発がん / プロテインホスファターゼ / 実験外科学

Outline of Final Research Achievements

Recently, to determine whether PP6 deficiency functions in carcinogenesis in vivo, we employed a mouse skin 2-stage carcinogenesis model. We found that a single DMBA application was sufficient to produce papillomas in Ppp6c-deficient skin. As such, ours was the first report that Ppp6c loss-of-function acts as a tumor promoter in mice. Here, we investigated effect of UVB radiation on mouse keratinocytes in which Ppp6c had been deleted. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. We concluded that Ppp6c loss-of-function in mouse skin showed hypersensitivity to UVB-induced squamous cell carcinoma. Our histochemical analyses suggest that Ppp6c deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53.

Research Products

• [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D-driven tumor promotion. (2018)
  • Author(s): Kurosawa K, Inoue Y, Kakugawa Y, Yamashita Y, Kanazawa K, Kishimoto K, Nomura M, Momoi Y, Sato I, Chiba N, Suzuki M, Ogoh H, Yamada H, Miura K, Watanabe T, Tanuma N, Tachi M, and Shima H
  • Journal Title: Cancer Science Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Associations of cigarette smoking and alcohol drinking with stomach cancer survival: A prospective patient cohort study in Japan (2018)
  • Author(s): Minami Yuko、Kanemura Seiki、Oikawa Tomoyuki、Suzuki Shinichi、Hasegawa Yasuhiro、Miura Koh、Nishino Yoshikazu、Kakugawa Yoichiro、Fujiya Tsuneaki
  • Journal Title: International Journal of Cancer Volume: - Issue: 5 Pages: 1072-1085
  • DOI: 10.1002/ijc.31408
  • Peer Reviewed / Open Access
• [Journal Article] Molecular and clinical features of the TP53 signature gene expression profile in early-stage breast cancer. (2018)
  • Author(s): Yamaguchi S, Takahashi S, Mogushi K, Izumi Y, Nozaki Y, Nomizu T, Kakugawa Y, Ishida T, Ohuchi N, Ishioka C, Kato S.
  • Journal Title: Oncotarget Volume: 9(18) Issue: 18 Pages: 14193-14206
  • DOI: 10.18632/oncotarget.24447
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative diagnostic imaging of cancer tissues by using phosphor-integrated dots with ultra-high brightness. (2017)
  • Author(s): Gonda Kohsuke
  • Journal Title: scientific reports Volume: - Issue: 1 Pages: 7509-7509
  • DOI: 10.1038/s41598-017-06534-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Drug delivery of oral anti-cancer fluoropyrimidine agents. (2017)
  • Author(s): Miura K, Shima H, Takebe N, Julie R, Satoh K, Kakugawa Y, Satoh M, Kinouchi M, Yamamoto K, Hasegawa Y, Kawai M, Kanazawa K, Fujiya T, Unno M and Katakura R.
  • Journal Title: Expert Opin.Drug Deliv Volume: 印刷中 Issue: 12 Pages: 1-12
  • DOI: 10.1080/17425247.2017.1316260
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Associations of obesity and physical activity with serum and intratumoral sex steroid hormone levels among postmenopausal women with breast cancer: analysis of paired serum and tumor tissue samples. (2017)
  • Author(s): Yoichiro Kakugawa, Hiroshi Tada, Masaaki Kawai, Takashi Suzuki, Yoshikazu Nishino, Seiki Kanemura, Takanori Ishida, Noriaki Ohuchi, Yuko Minami
  • Journal Title: Breast Cancer Res Treat Volume: 162（1） Issue: 1 Pages: 115-125
  • DOI: 10.1007/s10549-016-4094-3
  • Peer Reviewed / Open Access
• [Journal Article] Minimal impact of postmastectomy radiation therapy on locoregional recurrence for breast cancer patients with 1 to 3 positive lymph nodes in the modern treatment era (2017)
  • Author(s): Minoru Miyashita, Hiroshi Tada, Akihiko Suzuki, Gou Watanabe, Hisashi Hirakawa, Masakazu Amari, Yoichiro Kakugawa, Masaaki Kawai, Akihiko Furuta, Kaoru Sato, Ryuichi Yoshida, Akiko Ebata, Hironobu Sasano, Keiichi Jingu, Noriaki Ohuchi, Takanori Ishida
  • Journal Title: Surgical Oncology Volume: 26(2) Issue: 2 Pages: 163-170
  • DOI: 10.1016/j.suronc.2017.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA (2015)
  • Author(s): Hayashi K, Momoi Y , Tanuma N, Kishimoto A, Ogoh H, Kato H, Suzuki M, Sakamoto Y, Inoue Y, Nomura M, Kiyonari H, Sakayori M, Fukamachi K, Kakugawa Y, Yamashita Y, Ito S, Sato I, Suzuki A, Nishio M, Suganuma M, Watanabe T, and Shima H
  • Journal Title: Oncogene Volume: 印刷中 Issue: 35 Pages: 4647-55
  • DOI: 10.1038/onc.2014.398
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis. (2015)
  • Author(s): Kato H, Kurosawa K, Inoue Y, Tanuma N, Momoi Y, Hayashi K, Ogoh H, Nomura M, Sakayori M, Kakugawa Y, Yamashita Y, Miura K, Maemondo M, Katakura R, Ito S, Sato M, Sato I, Chiba N, Watanabe T, Shima H.
  • Journal Title: Cancer Lett. Volume: 365 Issue: 2 Pages: 223-228
  • DOI: 10.1016/j.canlet.2015.05.022
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Smoking and survival after breast cancer diagnosis in Japanese women: A prospective cohort study. (2015)
  • Author(s): Yoichiro Kakugawa, Masaaki Kawai, Yoshikazu Nishino, Kayoko Fukamachi,Takanori Ishida,Noriaki Ohuchi and Yuko Minami
  • Journal Title: Cancer Sci Volume: 106 Issue: 8 Pages: 1066-1074
  • DOI: 10.1111/cas.12716
  • Peer Reviewed / Open Access
• [Journal Article] Personality and breast cancer risk and survival: the Miyagi Cohort Study (2015)
  • Author(s): Yuko Minami, Toru Hosokawa, Naoki Nakaya, Yumi Sugawara, Yoshikazu Nishino, Yoichiro Kakugawa, Akira Fukao, Ichiro Tsuji
  • Journal Title: Breast Cancer Research and Treatment Volume: 150 Issue: 3 Pages: 675-684
  • DOI: 10.1007/s10549-015-3364-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The use of natural products in colorectal cancer drug discovery. (2015)
  • Author(s): Koh Miura, Masayuki Satoh, Makoto Kinouchi, Kuniharu Yamamoto, Yasuhiro Hasegawa, Yoichiro Kakugawa, Masaaki Kawai, Kiyoshi Uchimi, Hiroki Aizawa, Shinobu Ohnuma, Taiki Kajiwara, Hiroto Sakurai , Tsuneaki Fujiya
  • Journal Title: Expert opinion on drug discovery Volume: 10(4) Issue: 4 Pages: 411-426
  • DOI: 10.1517/17460441.2015.1018174
  • Peer Reviewed
• [Journal Article] Immunolocalization of thymidylate synthase as a favorable prognostic marker in estrogen receptor-positive breast carcinoma. (2015)
  • Author(s): Kiyoshi Takagi, Yasuhiro Miki, Yasuhiro Nakamura, Hisashi Hirakawa, Yoichiro Kakugawa, Goro Amano, Mika Watanabe, Takanori Ishida, Hironobu Sasano and Takashi Suzuki
  • Journal Title: Histology and histopathology Volume: 30 Pages: 1223-1232
  • Peer Reviewed
• [Presentation] Ppp6c は、マウス皮膚のがん抑制遺伝子として働く (2017)
  • Author(s): 黒沢是之、野村美有樹、角川陽一郎、山下洋二、三浦康、山田秀和、松浦一登、佐藤郁郎、田沼延公、渡邊利雄、島礼
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 新規皮膚がん抑制遺伝子Ppp6c変異は、変異型K-RASによる腫瘍発生を強く促進する (2016)
  • Author(s): 黒沢是之、田沼延公、角川陽一郎、山下洋二、三浦康、山田秀和、佐藤郁郎、野村美有樹、渡利雄、島礼
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市
  • Year and Date: 2016-10-06
• [Presentation] パーソナリティーと乳がん罹患・死亡リスクとの関連 (2016)
  • Author(s): 角川 陽一郎、西野 善一、吉田 薫、辻 一郎、南 優子
  • Organizer: 第24回 日本乳癌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-17
• [Presentation] 自己記入式質問紙調査による遺伝性乳がん卵巣がん症候群の拾い上げの現状と課題 (2016)
  • Author(s): 河合 賢朗、角川 陽一郎、五安城 芙由子、安田 有理、佐藤 馨、 古田 昭彦
  • Organizer: 第24回 日本乳癌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-17
• [Presentation] 皮膚Ppp6c欠損マウスは、UVB誘導皮膚扁平上皮発がんに高感受性となる (2015)
  • Author(s): 加藤浩之、田沼延公、三浦康、角川陽一郎、椎葉健一、山下洋二、林克剛、野村美有樹、佐藤郁郎、伊藤しげみ、渡邊利雄、島礼
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県・名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] 大腸癌における天然物を用いた抗がん剤開発の現況 (2015)
  • Author(s): 三浦康、島礼、佐藤賢一、山口壹範、田沼延公、角川陽一郎、佐藤正幸、木内誠、山本久仁治、長谷川康弘、河合賢朗、大沼忍、藤谷恒明
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県・名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Alcohol intake and breast cancer risk according to joint estrogen and progesterone receptor status:a case-control study. (2015)
  • Author(s): Yoko Takizawa, Masaaki Kawai, Yoshikazu Nishino, Yoichiro Kakugawa, Yuko Minami
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県・名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] 乳癌組織中ホルモン濃度と肥満度、運動習慣、飲酒との関連。 (2015)
  • Author(s): 角川陽一郎、河合賢朗、西野善一、南優子
  • Organizer: 第２３回 日本乳癌学会総会
  • Place of Presentation: 東京国際フォーラム（千代田区・東京都）
  • Year and Date: 2015-07-02