The crosstalk between cholesterol synthesis pathway and TGF-beta in pancreatic cancer

2012 Fiscal Year Final Research Report

• Project/Area Number: 22591525
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: ISHIKAWA Shinji 熊本大学, 医学部附属病院, 非常勤診療医師 (80419639)
• Co-Investigator(Kenkyū-buntansha): BABA Hideo 熊本大学, 大学院・生命科学研究部, 教授 (20240905) ; HORINO Kei 熊本大学, 医学部附属病院, 講師 (60452900) ; TAKAMORI Hiroshi 熊本大学, 医学部附属病院, 非常勤診療医師 (90363514)
• Project Period (FY): 2010 – 2012
• Keywords: スタチン / EZH2 / p27 / SREBP2 / HDAC5 / 大腸癌

Research Abstract

Although statins led better survival outcomes, the anti-proliferative effects inColorectal cancer (CRC) cells differ in statins (simvastatin >=fluvastatin > atorvastatin> pravastatin). Indeed, the recurrence rate of CRC patients with pravastatin had nodifference compared to patients without statin. As the underlying mechanism, statinsexcept pravastatin showed the anti-cancer effects by inhibiting EZH2-mediated genesilencing of p27KIP1. As a novel epigenetic anti-cancer strategy, a simvastatin plusclassII HDAC inhibitor synergistically induced the anti-proliferative effects byinhibiting EZH2-modulated HDAC5 induction. Thus, as a novel mechanism of statin-inducedanti-cancer effects, EZH2-mediated epigenetic mechanism was identified. Although statinmay lead to survival benefits in CRC patients, its anti-cancer effects differ in statins,suggesting that the kind of statins should be considered in clinical settings.

Research Products

• [Journal Article] Carcinogenesis of IntraductalPapillary Mucinous Neoplasm of thePancreas: Loss of MicroRNA-101Promotes Overexpression of HistoneMethyltransferase EZH2 (2012)
  • Author(s): Nakahara O,Takamori H,Iwatsuki M,Baba Y,Sakamoto Y,Tanaka H,Chikamoto A,Horino K,Beppu T,Kanemitsu K,Honda Y,Iyama K,Baba H
  • Journal Title: Ann Surg Oncol Volume: 3 Pages: 565-71
  • DOI: DOI:10.1245/s10434-011-2068-6
  • Peer Reviewed
• [Journal Article] Cutaneous metastases secondary topancreatic cancer (2012)
  • Author(s): Horino K, Takamori H, Ikuta Y,Nakahara O, Chikamoto A, Ishiko T,Beppu T, Baba H
  • Journal Title: World J Gastrointestinal Oncol Volume: 4 Pages: 176-180
  • DOI: DOI:10.4251/wjgo.v4.i7.176
  • Peer Reviewed
• [Journal Article] Perioperative intra -arterial andsystemic chemotherapy for pancreaticcancer (2011)
  • Author(s): Takamori H, Kanemitsu K, Hirota M,Ikeda O, Tanaka H, Beppu T,Yamashita Y, Oya N, Baba H
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 1110-5
  • DOI: DOI:10.1245/s10434-010-1384-6
  • Peer Reviewed
• [Journal Article] Clinical significance ofdihydropyrimidine dehydrogenase andthymidylate synthase expression inpatients with pancreatic cancer (2010)
  • Author(s): Nakahara O, Takamori H, Tanaka H,Sakamoto Y, Ikuta Y, Furuhashi S,Watanabe M, Beppu T, Hirota M,Kanemitsu K, Baba H
  • Journal Title: Int J Clin Oncol Volume: 15 Pages: 39-45
  • DOI: DOI:10.1007/s10147-009-0008-2
  • Peer Reviewed
• [Journal Article] Chronic pancreatitis in mice bytreatment withcholinedeficientethioninesupplemented diet (2010)
  • Author(s): Ida S,Ohmuraya M,Hirota M,Ozaki N,Hiramatsu S,Uehara H,Takamori H,Araki K,Baba H,Yamamura K
  • Journal Title: Exp Anim Volume: 59 Pages: 421-9
  • Peer Reviewed
• [Journal Article] The role of oxysterol bindingprotein related protein 5 inpancreatic cancer (2010)
  • Author(s): Ishikawa S,Nagai Y, Masuda T, Nakamura T,Imamura Y,Takamori H,Hirota M, Funakosi A,Fukushima M,Baba H
  • Journal Title: Cancer Sci Volume: 101 Pages: 898-905
  • Peer Reviewed
• [Journal Article] Serine protease inhibitor Kazaltype 1 and epidermal growth factorreceptor are expressed in pancreatictubular adenocarcinoma. Intraductalpapillary mucinous neoplasm, andpancreatic intraepithelialneoplasia
  • Author(s): Ozaki N,Ohmuraya M,Ida S, Hashimoto D,Ikuta Y,Chikamoto A,Hirota M,Baba H
  • Journal Title: J Gastroenteol (Published Online)
  • DOI: DOI:10.1007/s00534 -012-0587-6
  • Peer Reviewed
• [Presentation] 膵 IPMN の悪性化における EZH2 の臨床的意義 (2012)
  • Author(s): 黒木秀幸、林 洋光、中川茂樹、橋本大輔、生田義明、近本 亮、別府 透、馬場秀夫
  • Organizer: 第26回日本消化器癌発生学会
  • Place of Presentation: ルネッサンスリゾートナルト(徳島県)
  • Year and Date: 2012-11-15
• [Presentation] 通常型膵癌における性差による治療反応性の比較 (2012)
  • Author(s): 高森啓史、中原 修、生田義明、黒木秀幸、近本 亮、土居浩一、石河隆敏、別府 透、馬場秀夫
  • Organizer: 2012 年度日本消化器関連学会週間
  • Place of Presentation: 神戸国際展示場 (兵庫県)
  • Year and Date: 2012-10-12
• [Presentation] stage 4a, 4b 膵癌に対する集学的治療の検討 (2012)
  • Author(s): 高森啓史、中原 修、生田義明、新田英利、今井克憲、林 洋光、近本 亮、土居浩一、別府 透、馬場秀夫
  • Organizer: 第67回日本消化器外科学会
  • Place of Presentation: ANA クラウンプラザホテル富山(富山県)
  • Year and Date: 2012-07-20
• [Presentation] 膵癌に治癒は望めるか?-5 年生存者からの検討 (2012)
  • Author(s): 高森啓史、生田義明、中原 修、橋本大輔、黒木秀幸、馬場秀夫
  • Organizer: 第43回日本膵臓学会
  • Place of Presentation: ホテルメトロポリタン山形(山形県)
  • Year and Date: 2012-06-29
• [Presentation] 膵癌の前癌病変(IPMN)における悪性化の機序解明‐miR-101 と EZH2 の発現の観点から‐ (2012)
  • Author(s): 中原 修、高森啓史、黒木秀幸、生田義明、近本 亮、別府 透、馬場秀夫
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張メッセ国際会議場(千葉県)
  • Year and Date: 2012-04-12
• [Presentation] 切除適応膵癌に対する周術期補助化学療法施行例の予後因子解析からみた治療戦略の方向性 (2012)
  • Author(s): 高森啓史、生田義明、中原 修、黒木秀幸、近本 亮、土居浩一、石河隆敏、別府 透、馬場秀夫
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張メッセ国際会議場(千葉県)
  • Year and Date: 2012-04-12
• [Presentation] Use of the round ligament andomental flap to prevent pancreaticfistula, sequential delayed intra-abdominal hemorrhage afterpancreaticoduodenectomy -doublewrapping method (2011)
  • Author(s): Takamori H, Tanaka H, Nakahara O, Abe S, Chikamoto A, Horino K, Beppu T,Baba H
  • Organizer: 第44回万国外科学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-08-30
• [Presentation] Utility of a critical pathway forpancreaticoduodenectomy (2011)
  • Author(s): Horino K, Takamori H, Nakahara O,Chikamoto A, Tanaka H, Ishiko T, Beppu T, Baba H
  • Organizer: INTERNATIONAL SURGICAL WEEK 2011(第44回万国外科学会)
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-08-28
• [Presentation] 膵頭十二指腸切除術前の減黄術と合併症 (2011)
  • Author(s): 堀野 敬、高森啓史、田中 洋、阿部真也、中原 修、古橋 聡、増田稔郎、近本 亮、石河隆敏、別府 透、馬場秀夫
  • Organizer: 第66回日本消化器外科学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-07-15
• [Presentation] 浸潤性膵管癌に対する治療戦略 (2011)
  • Author(s): 高森啓史、 田中 洋、阿部真也、中原修、堀野 敬、増田稔郎、近本 亮、石河隆敏、別府 透、馬場秀夫
  • Organizer: 第66回日本消化器外科学会総会
  • Place of Presentation: 名古屋国際会議場 (愛知県)
  • Year and Date: 2011-07-14
• [Presentation] 膵 IPMN の癌化における EZH2 とmicroRNA-101 の関与 (2011)
  • Author(s): 中原 修、 高森啓史、 生田義明、 別府 透、馬場秀夫
  • Organizer: 第20回日本癌病態治療研究会
  • Place of Presentation: 東京大学医学部教育研究棟(東京都)
  • Year and Date: 2011-06-17
• [Presentation] Carcinogenesis of intraductalpapillary mucinous neoplasm of thepancreas: Loss of microRNA-101promotes overexpression of histonemethyltransferase EZH2 (2011)
  • Author(s): Nakahar O, Takamori H, Sakamoto Y,Tanaka H, Chikamoto A, Horino K, BeppuT, Honda Y, Iyama K, Baba H
  • Organizer: AACR102nd Annual Meeting 2011
  • Place of Presentation: Orange County ConventionCenter Orlando(アメリカ)
  • Year and Date: 2011-04-02
• [Presentation] Loss of microRNA-101 leads tocarcinogenesis of pancreaticintraduvtal papillary mucinousneoplasms (IPMN)throuchoverexpression of histonmethyltaransferase EZH2 (2010)
  • Author(s): 中原 修、 高森啓史、 堀野 敬、 田中 洋、井田 智、 古橋 聡、 阿部真也、 別府 透、馬場秀夫
  • Organizer: 第21回消化器癌発生学会
  • Place of Presentation: 軽井沢プリンスホテルウエスト(長野県)
  • Year and Date: 2010-11-18
• [Presentation] Preoperative biliary drainageincreases the incidence of surgicalsite infection afterpancreaticoduodenectomy (2010)
  • Author(s): Horino K, Baba H
  • Organizer: 20th World Congress of theInternational Association ofSurgeons
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2010-10-23
• [Presentation] Overexpression of EGFR in theexocrine pancreas induces a chronicpancreatitis (2010)
  • Author(s): Ida S, Ohmuraya M, Nakahara O,Furuhashi S, Abe S, Tanaka H,Horino K, Takamori H, Beppu T,Baba H
  • Organizer: 9th International Conference of theAsian Clinical Oncology Society
  • Place of Presentation: Gifu grand Hotel(岐阜県)
  • Year and Date: 2010-08-25
• [Presentation] Single Drain is enough forpancreatic reconstruction afterpancreaticoduodenectomy (2010)
  • Author(s): Horino K, Takamori H, Tanaka H,Akaboshi S, Ozaki N, Nakahara O,Furuhashi S, Ida S, Abe S, Beppu T,Baba H
  • Organizer: 9th 第14回国際膵臓学会・第41回日本膵臓学会合同会議
  • Place of Presentation: 福岡国際会議場(福岡県)
  • Year and Date: 2010-07-11
• [Presentation] Cerulein induced acute pancreatitissuppress the mTOR activity (2010)
  • Author(s): Ida S, Ohmuraya M,Hirota M,Nakahara O, Furuhashi S, Abe S,Tanaka H, Horino K, Takamori H,Beppu T, Baba H
  • Organizer: 第14回国際膵臓学会・第41回日本膵臓学会合同会議
  • Place of Presentation: 福岡国際会議場(福岡県)
  • Year and Date: 2010-07-11
• [Book] Diseasesand Health Implications (2012)
  • Author(s): Hashimoto D, Hirota M, Takamori H,Baba H
  • Total Pages: 90-107
  • Publisher: Autophagy in PancreaticDiseases, Pancreas: Anatomy