Identification of biomarkers for biliary tract cancer by proteomic approaches

• Project/Area Number: 17H04287
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: International University of Health and Welfare
• Principal Investigator: Miyazaki Masaru 国際医療福祉大学, 大学病院, 教授 (70166156)
• Co-Investigator(Kenkyū-buntansha): 高野 重紹 千葉大学, 大学院医学研究院, 助教 (20436380) ; 野島 広之 千葉大学, 医学部附属病院, 助教 (10507320) ; 吉富 秀幸 千葉大学, 大学院医学研究院, 准教授 (60375631) ; 加藤 厚 国際医療福祉大学, 医学部, 教授 (70344984) ; 大塚 将之 千葉大学, 大学院医学研究院, 教授 (90334185) ; 賀川 真吾 千葉大学, 医学部附属病院, 助教 (90507302)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: 胆道癌 / バイオマーカー / 膵癌 / 外科

Outline of Final Research Achievements

Using TMT labelling and LC-MS/MS, we performed comparative analyses of pre- and postoperative sera from pancreatic cancer (PDAC) patients to identify specific serum biomarkers for PDAC. C4b-binding protein a-chain (C4BPA) was identified, and serum C4BPA levels in patients with PDAC were significantly higher than those in healthy controls as well as in patients with pancreatitis and other malignancies including biliary tract cancers (BTC) (P<0.001). The area under the ROC curve (AUC) was 0.860 for C4BPA, 0.846 for CA19-9 in PDAC vs non-cancer individuals. Next, we identified novel biomarkers in BTC using the ClinProtTM system. We developed an enzyme immunoassay for a 4204 Da peptide identified as thrombin light chain. Serum thrombin light chain was measured by the ELISA, and its levels were significantly greater in BTC than in benign biliary disease and healthy controls (P<0.001). The sandwich ELISA is useful for measurement of serum thrombin light chain levels in clinical setting.

Academic Significance and Societal Importance of the Research Achievements

様々なproteomicsの手技を用いた血清蛋白の網羅的解析から見出された候補蛋白の同定を行った。これらの値を測定することで、既存の血清腫瘍マーカーや画像による早期診断の困難な代表的疾患である、膵胆道癌の早期診断に結びつく可能性があり、社会的意義のある研究であったと考える。今後の重要な課題であるこれらの蛋白の血清発現量を高感度に測定する検査系を構築することで、臨床応用の可能性がより高まると考える。

Research Products

• [Journal Article] Long-term outcomes and significance of preoperative lymphocyte-to-monocyte ratio as a prognostic indicator in patients with invasive pancreatic neoplasms after repeat pancreatectomy (2020)
  • Author(s): Takano Shigetsugu、Yoshitomi Hideyuki、Kagawa Shingo、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Suzuki Daisuke、Sakai Nozomu、Mishima Takashi、Nakadai Eri、Miyazaki Masaru、Ohtsuka Masayuki
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 111-111
  • DOI: 10.1186/s12885-020-6602-4
  • Peer Reviewed / Open Access
• [Journal Article] Is hepatic artery coil embolization useful in distal pancreatectomy with en bloc celiac axis resection for locally advanced pancreatic cancer? (2019)
  • Author(s): Ueda A, Sakai N, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Takano S, Suzuki D, Kagawa S, Mishima T, Nakadai E, Miyazaki M, Ohtsuka M.
  • Journal Title: World J Surg Oncol. 124 Volume: 17 Issue: 1 Pages: 124-124
  • DOI: 10.1186/s12957-019-1667-8
  • Peer Reviewed / Open Access
• [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] The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer Stemness and Is Associated with Poor Prognosis in Intrahepatic Cholangiocarcinoma (2019)
  • Author(s): Sugiura Kensuke、Mishima Takashi、Takano Shigetsugu、Yoshitomi Hideyuki、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Takada Mamoru、Miyazaki Masaru、Ohtsuka Masayuki
  • Journal Title: The American Journal of Pathology Volume: 189 Issue: 9 Pages: 1863-1877
  • DOI: 10.1016/j.ajpath.2019.05.014
  • 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] Benchmarks in Pancreatic Surgery (2019)
  • Author(s): Sanchez-Velazquez Patricia、Muller Xavier、Malleo Giuseppe、Miyazaki M、et al.
  • Journal Title: Annals of Surgery Volume: Feb27 Issue: 2 Pages: 211-218
  • DOI: 10.1097/sla.0000000000003223
  • Peer Reviewed / Int'l Joint Research
• [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] Outcomes of 1,639 hepatectomies for non-colorectal non-neuroendocrine liver metastases: a multicenter analysis. (2018)
  • Author(s): Sano K, Yamamoto M, Mimura T, Endo I, Nakamori S, Konishi M, Miyazaki M, Wakai T, Nagino M, Kubota K, Unno M, Sata N, Yamamoto J, Yamaue H, Takada T; Japanese Society of Hepato-Biliary-Pancreatic Surgery.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Issue: 11 Pages: 465-475
  • DOI: 10.1002/jhbp.587
  • 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] Impact of Biliary Drainage on Multidetector-Row Computed Tomography on R0 Resection of Perihilar Cholangiocarcinoma (2018)
  • Author(s): Hosokawa Isamu、Shimizu Hiroaki、Yoshitomi Hideyuki、Furukawa Katsunori、Takayashiki Tsukasa、Miyazaki Masaru、Ohtsuka Masayuki
  • Journal Title: World Journal of Surgery Volume: 42 Issue: 11 Pages: 3676-3684
  • DOI: 10.1007/s00268-018-4654-2
  • Peer Reviewed
• [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
• [Presentation] 網羅的secretome解析による膵癌周囲間質を介在する分泌蛋白の同定 (2019)
  • Author(s): 島崎 怜理、高野 重紹、佐藤 守、吉富 秀幸、野村 文夫、大塚 将之
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] The clinical impact and analysis for neoadjuvant chemotherapy against borderline resectable pancreatic cancer: gemcitabine plus S-1 vs gemcitabine plus nab-paclitaxel. (2019)
  • Author(s): Shigetsugu Takano, Hideyuki Yoshitomi, Shingo Kagawa, Furukawa Katsunori, Tsukasa Takayashiki, Satoshi Kuboki, Daisuke Suzuki, Nozomu Sakai, Takashi Mishima, Eri Nakadai, Masayuki Ohtsuka.
  • Organizer: AACR special conference Pancreatic Cancer: Advances in Science and Clinical Care
  • Int'l Joint Research
• [Presentation] A novel serum biomarker for pancreatic cancer, C4BPA is identified by comprehensive quantitative proteomics analysis (2017)
  • Author(s): Shigetsugu Takano, Kazuyuki Sogawa, Hideyuki Yoshitomi, Masaru Miyazaki, Fumio Nomura, Masayuki Ohtsuka
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 膵癌早期診断マーカーとしての血清C4BPA値の意義 (2017)
  • Author(s): 高野重紹、曽川一幸、吉富秀幸、清水宏明、古川勝規、高屋敷 吏、久保木 知、鈴木大亮、酒井 望、賀川真吾、野島広之、野村文夫、宮崎 勝、大塚将之
  • Organizer: 第117回日本外科学会定期学術集会