A new approach for avoiding age-related risks after extended hepatectomy by targeting Pin1.

• Project/Area Number: 17K10661
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Chiba University
• Principal Investigator: Kuboki Satoshi 千葉大学, 医学部附属病院, 講師 (50571410)
• Co-Investigator(Kenkyū-buntansha): 野島 広之 千葉大学, 医学部附属病院, 助教 (10507320) ; 酒井 望 千葉大学, 医学部附属病院, 助教 (70436385) ; 大塚 将之 千葉大学, 大学院医学研究院, 教授 (90334185)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 高齢者 / 拡大肝切除 / 肝再生 / Pin1 / NF-kappaB / STAT3 / 高齢肝 / NF-kappaB-p65 / 微小循環障害 / 肝切除 / 加齢

Outline of Final Research Achievements

Liver regeneration was suppressed and the incidence of severe postoperative complications was increased in elderly patients after extended hepatectomy. In vivo, NF-kappaB and STAT3 activation was suppressed in aged mice after extended hepatectomy, resulted in delayed liver regeneration. Pin1 was essential for NF-kappaB and STAT3 activation after hepatectomy. Moreover, Pin1 was decreased in aged mice after extended hepatectomy, resulting in delayed liver regeneration in aged mice. In vitro, knockdown of Pin1 in mice normal hepatocytes, AML-12, inhibited hepatocyte proliferation. Therefore, decreased expression of Pin1 in the elderly patients after extended hepatectomy is the main factor for delayed liver regeneration after extended hepatectomy.

Academic Significance and Societal Importance of the Research Achievements

近年の高齢化社会に伴い、拡大肝切除術を受ける高齢者が増加しているが、高齢者では肝再生が抑制され、重症合併症が増加することが示された。本研究では高齢者における術後肝再生遅延機序の詳細を解明した。現在は高齢者では残肝率を十分に確保することが術後重症合併症回避のための唯一の方法であるが、この結果を応用することでより少ない残肝率でもPin1を介した転写因子活性亢進を誘導する治療を併用することにより、術後重症合併症を回避することが出来ると考えられ、より多くの高齢者が肝切除術の適応となるため、その社会的意義は非常に高いと考える。

Research Products

• [Journal Article] OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma (2019)
  • Author(s): Ashizawa Y, Kuboki S, Nojima H, Takano S, Ohtsuka M, et al
  • Journal Title: Hepatology Communications Volume: 3 Issue: 7 Pages: 954-970
  • DOI: 10.1002/hep4.1361
  • Peer Reviewed / Open Access
• [Journal Article] Feasibility and safety of distal pancreatectomy with en bloc celiac axis resection (DP-CAR) combined with neoadjuvant therapy for borderline resectable and unresectable pancreatic body/tail cancer. (2019)
  • Author(s): Yoshitomi H, Sakai N, Kagawa S, Takano S, Ueda A, Kato A, Furukawa K, Takayashiki T, Kuboki S, Miyzaki M, Ohtsuka M
  • Journal Title: Langenbecks Arch Surg. Volume: In press Issue: 4 Pages: 1-8
  • DOI: 10.1007/s00423-019-01775-0
  • Peer Reviewed
• [Journal Article] A case of successfully resected metachronous gastric and gallbladder metastases from pancreatic body cancer. (2019)
  • Author(s): Takahashi M, Yoshitomi H, Kato A, Furukawa K, Takayashiki T, Kuboki S, Takano S, Sugiura K, Kawasaki K, Miyazaki M, Ohtsuka M.
  • Journal Title: Surg Case Rep. Volume: 5 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s40792-019-0581-1
  • Peer Reviewed
• [Journal Article] Roles of Pin1 as a Key Molecule for EMT Induction by Activation of STAT3 and NF-κB in Human Gallbladder Cancer. (2019)
  • Author(s): Nakada S, Kuboki S, Nojima H, Yoshitomi H, Furukawa K, Takayashiki T, Takano S, Miyazaki M, Ohtsuka M.
  • Journal Title: Ann Surg Oncol. Volume: 26 Issue: 3 Pages: 907-917
  • DOI: 10.1245/s10434-018-07132-7
  • Peer Reviewed
• [Journal Article] Additional effect of perioperative, compared with preoperative, immunonutrition after pancreaticoduodenectomy: A randomized, controlled trial. (2019)
  • Author(s): Miyauchi Y, Furukawa K, Suzuki D, Yoshitomi H, Takayashiki T, Kuboki S, Miyazaki M, Ohtsuka M.
  • Journal Title: Additional effect of perioperative, compared with preoperative, immunonutrition after pancreaticoduodenectomy: A randomized, controlled trial. Volume: 61 Pages: 69-75
  • DOI: 10.1016/j.ijsu.2018.11.028
  • Peer Reviewed
• [Journal Article] Outcomes of left trisectionectomy and right hepatectomy for perihilar cholangiocarcinoma. (2019)
  • Author(s): Hosokawa I, Shimizu H, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Koda K, Miyazaki M, Ohtsuka M.
  • Journal Title: HPB (Oxford). Volume: 21 Issue: 4 Pages: 489-498
  • DOI: 10.1016/j.hpb.2018.08.017
  • Peer Reviewed
• [Journal Article] Conversion surgery with gemcitabine plus nab-paclitaxel for locally advanced unresectable pancreatic cancer: A case report. (2018)
  • Author(s): Okura R, Takano S, Yokota T, Yoshitomi H, Kagawa S, Furukawa K, Takayashiki T, Kuboki S, Suzuki D, Sakai N, Nojima H, Mishima T, Miyazaki M, Ohtsuka M.
  • Journal Title: Mol Clin Oncol. Volume: 9 Pages: 389-393
  • DOI: 10.3892/mco.2018.1688
  • Peer Reviewed / Open Access
• [Journal Article] Expression of annexin II and stromal tenascin C promotes epithelial to mesenchymal transition and correlates with distant metastasis in pancreatic cancer. (2018)
  • Author(s): Yoneura N, Takano S, Yoshitomi H, Nakata Y, Shimazaki R, Kagawa S, Furukawa K, Takayashiki T, Kuboki S, Miyazaki M, Ohtsuka M.
  • Journal Title: Int J Mol Med. Volume: 42 Pages: 821-830
  • DOI: 10.3892/ijmm.2018.3652
  • Peer Reviewed / Open Access
• [Journal Article] Novel treatment strategy with radiofrequency ablation and surgery for pregnant patients with hepatocellular carcinoma: a case report. (2018)
  • Author(s): Matsuo M, Furukawa K, Shimizu H, Yoshitomi H, Takayashiki T, Kuboki S, Takano S, Suzuki D, Sakai N, Kagawa S, Nojima H, Ohsuka M.
  • Journal Title: Surg Case Rep. Volume: 4 Issue: 1 Pages: 43-43
  • DOI: 10.1186/s40792-018-0434-3
  • Peer Reviewed / Open Access
• [Journal Article] A New Proposal of Criteria for the Future Remnant Liver Volume in Older Patients Undergoing Major Hepatectomy for Biliary Tract Cancer. (2018)
  • Author(s): Watanabe Y, Kuboki S, Shimizu H, Ohtsuka M, Yoshitomi H, Furukawa K, Miyazaki M.
  • Journal Title: Annals of Surgery Volume: 267 Issue: 2 Pages: 338-345
  • DOI: 10.1097/sla.0000000000002080
  • Peer Reviewed
• [Presentation] 高齢胆道癌患者に対する拡大肝切除術を安全に施行するための至適残肝率の再考 (2020)
  • Author(s): 久保木 知
  • Organizer: 第120回日本外科学会
• [Presentation] Small-for-size graftにおける脾摘の類洞内皮障害軽減効果に関するmolecular mechanismの解明 (2019)
  • Author(s): 久保木 知
  • Organizer: 第37回日本肝移植学会
• [Presentation] 高齢胆道癌患者に対する拡大肝切除術を安全に施行するための新たな残肝率基準の提唱 (2018)
  • Author(s): 久保木 知
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] Multidisciplinary treatment combined with neoadjuvant downsizing chemotherapy and aggressive regional lymph node dissection to achieve R0 resection improves prognosis in patients with advanced intrahepatic cholangiocarcinoma. (2018)
  • Author(s): 久保木 知
  • Organizer: 13th IHPBA World Congress
  • Int'l Joint Research
• [Presentation] 肝門部領域胆管癌に対する手術を加味した適切な術前減黄strategyの検証 (2018)
  • Author(s): 久保木 知
  • Organizer: 第54回日本胆道学会学術集会
• [Presentation] 進行胆嚢癌に対する根治的外科切除を目指した集学的治療戦略 (2018)
  • Author(s): 久保木 知
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 進行肝内胆管癌に対する術前化学療法の施行およびR0切除を目指した積極的外科治療の意義を再考する (2018)
  • Author(s): 久保木 知
  • Organizer: 第16回日本消化器外科学会大会
• [Presentation] 残肝容量不足時のshare stress増強に伴う類洞内皮障害軽減に対する脾摘の意義に関する基礎的研究 (2017)
  • Author(s): 久保木 知、清水 宏明、吉富 秀幸、古川 勝規、高屋敷 吏、高野 重紹、鈴木 大亮、酒井 望、賀川 真吾、野島 広之、宮崎 勝、大塚 将之
  • Organizer: 第35回日本肝移植研究会
• [Presentation] 高齢ドナー肝における肝障害増強・肝再生抑制機序に関する基礎的・臨床的検討 (2017)
  • Author(s): 久保木知、吉富 秀幸、古川 勝規、高屋敷 吏、仲田 真一郎、松尾 めぐみ、川崎 圭史、大塚 将之
  • Organizer: 第53回日本移植学会学術集会
• [Presentation] 術後肝再生シグナル誘導に関するkey moleculeとしてのPin1の有用性 (2017)
  • Author(s): 久保木 知、宮崎 勝、大塚 将之
  • Organizer: 第15回日本消化器外科学会大会
• [Presentation] 高齢胆道癌患者に対する拡大肝切除術を安全に施行するための至適残肝率の再考 (2017)
  • Author(s): 久保木 知、渡邉 善寛、野島 広之、吉富 秀幸、 古川 勝規、 高屋敷 吏、高野 重紹、鈴木 大亮、酒井 望、賀川 真吾、三島 敬、宮崎 勝、大塚 将之
  • Organizer: 第79回日本臨床外科学会総会