Mechanism of cancer progression mediated by IL-32-Gankyrin axis in intrahepatic cholangiocarcinoma

• Project/Area Number: 19K09190
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Chiba University
• Principal Investigator: Mishima Takashi 千葉大学, 医学部附属病院, 助教 (70802560)
• Co-Investigator(Kenkyū-buntansha): 野島 広之 帝京大学, 医学部, 講師 (10507320) ; 高野 重紹 千葉大学, 医学部附属病院, 講師 (20436380) ; 久保木 知 千葉大学, 大学院医学研究院, 講師 (50571410) ; 大塚 将之 千葉大学, 大学院医学研究院, 教授 (90334185)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝内胆管癌 / IL-32 / Gankyrin

Outline of Research at the Start

肝内胆管癌は再発率が高く、化学療法の効果があまり期待できない事が多い。この原因のひとつとして、癌幹細胞が重要な役割をはたすと言われている。我々はこの癌幹細胞の維持にGankyrinという物質が関連しているということを以前の研究で見出したが、これを調節する因子は今のところわかっていない。そこで、最近癌との関連が注目されているIL-32という物質に着目した。これはよくGankryinと似た働きをしており、Gankyrinの働きを調節している可能性を考えている。よって、本研究の目的ははGankryinを調節する因子としてのIL-32の働きを明らかにし、今後の治療の標的となりうるかを検討する事である。

Outline of Final Research Achievements

Results of the immunohistochemical staining of 75 resected intrahepatic cholangiocarcinoma cases in our department revealed that the group with high gankyrin expression in tumor cells had a significantly worse prognosis. However, the prognosis of the group with high interleukin-32 (IL-32) expression in tumor cells was not different from the group with low IL-32 expression.
However, in the evaluation of IL-32 expression in peritumoral tissues, the group with high IL-32 expression in peritumoral tissues (tumor stroma) had a significantly worse prognosis compared to the group with low IL-32 expression (p = 0.05). Furthermore, many of the patients with high IL-32 expression in the peritumoral tissues had vascular invasion, suggesting that IL-32 may influence the maintenance of tumor cells’ malignancy potential in a paracrine manner.

Academic Significance and Societal Importance of the Research Achievements

IL-32とGankyrinの関連は明らかには出来ていないものの、IL-32は肝内胆管癌において、腫瘍周囲から悪性度の維持などの影響を及ぼしている可能性がある。IL-32は癌腫によりその働きは違い、悪性度を高めているものから弱めるものまで様々である。しかし、肝内胆管癌においては悪性度を高める方向に働いている事が本研究により示唆された。今後も細胞レベルでの研究を続けることで、新たな治療ターゲットの一つとなる可能性が示された。

Research Products

• [Journal Article] Fat signal fraction assessed with MRI predicts hepatic recurrence following hepatic resection for colorectal liver metastases (2022)
  • Author(s): Sakai Nozomu、Hayano Koichi、Mishima Takashi、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Takano Shigetsugu、Kawasaki Yohei、Matsubara Hisahiro、Ohtsuka Masayuki
  • Journal Title: Langenbeck's Archives of Surgery Volume: - Issue: 5 Pages: 1981-1989
  • DOI: 10.1007/s00423-022-02482-z
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of mismatch repair deficient biliary tract cancer: Role of morphological features and host immune response detected by routine hematoxylin-eosin staining (2021)
  • Author(s): Suda R, Sakai N, Matsushita K, Ishige T, Kawasaki Y, Shiko Y, Furukawa K, Mishima T, Nakadai E, Ohtsuka M
  • Journal Title: J Hepatobiliary Pancreat Sc Volume: 28 Issue: 8 Pages: 680-691
  • DOI: 10.1002/jhbp.988
  • Peer Reviewed / Open Access
• [Journal Article] Solid serous neoplasm of the pancreas with locally aggressive behaviors (2021)
  • Author(s): Kouchi Yusuke、Yamashita Kazushi、Harada Sakurako、Shinomiya Yoshiki、Mishima Takashi、Takano Shigetsugu、Matsusaka Keisuke、Nasu Katsuhiro、Ikeda Jun‐ichiro、Ohtsuka Masayuki、Kishimoto Takashi
  • Journal Title: Pathology International Volume: 71 Issue: 11 Pages: 795-797
  • DOI: 10.1111/pin.13163
  • Peer Reviewed
• [Journal Article] Outcome of interventional radiology for delayed postoperative hemorrhage in hepatobiliary and pancreatic surgery (2020)
  • Author(s): Sakai Nozomu、Yoshitomi Hideyuki、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Takano Shigetsugu、Suzuki Daisuke、Kagawa Shingo、Mishima Takashi、Nakadai Eri、Ohtsuka Masayuki
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 35 Issue: 12 Pages: 2264-2272
  • DOI: 10.1111/jgh.15140
  • Peer Reviewed / Open Access
• [Journal Article] High expression of Kruppel‐like factor 5 is associated with poor prognosis in patients with colorectal cancer (2020)
  • Author(s): Takagi Yutaka、Sakai Nozomu、Yoshitomi Hideyuki、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Takano Shigetsugu、Suzuki Daisuke、Kagawa Shingo、Mishima Takashi、Nakadai Eri、Miyauchi Hideaki、Matsubara Hisahiro、Ohtsuka Masayuki
  • Journal Title: Cancer Science Volume: 111 Issue: 6 Pages: 2078-2092
  • DOI: 10.1111/cas.14411
  • Peer Reviewed
• [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] Needle tract seeding recurrence of pancreatic cancer in the gastric wall with paragastric lymph node metastasis after endoscopic ultrasound-guided fine needle aspiration followed by pancreatectomy: a case report and literature review (2020)
  • Author(s): Sato Nami、Takano Shigetsugu、Yoshitomi Hideyuki、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Suzuki Daisuke、Sakai Nozomu、Kagawa Shingo、Mishima Takashi、Nakadai Eri、Mikata Rintaro、Kato Naoya、Ohtsuka Masayuki
  • Journal Title: BMC Gastroenterology Volume: 20 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12876-020-1159-x
  • Peer Reviewed / Open Access
• [Journal Article] Needle tract seeding recurrence of pancreatic cancer in the gastric wall with paragastric lymph node metastasis after endoscopic ultrasound-guided fine needle aspiration followed by pancreatectomy: a case report and literature review. (2020)
  • Author(s): Sato N, Takano S, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Suzuki D, Sakai N, Kagawa S, Mishima T, Nakadai E, Mikata R, Kato N, Ohtsuka M.
  • Journal Title: BMC Gastroenterol. Volume: 20 Pages: 13-13
  • 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] 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] Successful treatment of a locally advanced unresectable pancreatic cancer patient with interstitial pneumonitis by conversion surgery following gemcitabine plus nab-paclitaxel chemotherapy: A case report. (2019)
  • Author(s): Yokota T, Takano S, Yoshitomi H, Kagawa S, Furukawa K, Takayashiki T, Kuboki S, Suzuki D, Sakai N, Nojima H, Mishima T, Nakadai E, Ohtsuka M.
  • Journal Title: Mol Clin Oncol. Volume: 10 Pages: 419-424
  • DOI: 10.3892/mco.2019.1807
  • Peer Reviewed
• [Presentation] 胆嚢癌におけるSTAT3およびNF-kB活性亢進を介したEMT誘導に関するPin1の意義 (2021)
  • Author(s): 仲田 真一郎, 久保木 知, 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, 細川 勇, 三島 敬, 小西 孝宣, 宮崎 勝, 大塚 将之
  • Organizer: 第121回日本外科学会定期学術集会
• [Presentation] 肝内胆管癌の外科治療の現状と課題:成績向上はあるのか? 治療成績向上を目指した肝内胆管癌に対する根治手術と化学療法を組み合わせた集学的治療成績の再考 (2021)
  • Author(s): 久保木 知, 古川 勝規, 高屋敷 吏, 高野 重紹, 鈴木 大亮, 酒井 望, 賀川 真吾, 細川 勇, 三島 敬, 小西 孝宜, 大塚 将之
  • Organizer: 第121回日本外科学会定期学術集会
• [Presentation] 進行胆嚢癌におけるPD-L1発現の臨床的意義 (2021)
  • Author(s): 佐藤 豊, 久保木 知, 古川 勝規, 高屋敷 吏, 高野 重紹, 鈴木 大亮, 酒井 望, 賀川 真吾, 細川 勇, 三島 敬, 小西 孝宜, 大塚 将之
  • Organizer: 第121回日本外科学会定期学術集会
• [Presentation] Analysis of correlation between resection margin and recurrence in patients with IPMN (2020)
  • Author(s): Takashi Mishima, Shigetsugu Takano, Katsunori furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Daisuike Suzuki, Nozomu Sakai, Shingo Kagawa, Isamu Hosokawa, Takanori Konishi, Masayuki Ohtsuka
  • Organizer: The 32nd Meeting of Japanese Society of Hepato Billiary Pancreatic Surgery
• [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] C4BPA identified as a novel biomarker is associated with favorable outcome of patients with pancreatic cancer. (2019)
  • Author(s): Kosuke Sasaki, Shigetsugu Takano, Hideyuki Yoshitomi, Kazuyuki Sogawa, Shingo Kagawa, Katsunori Furukawa, 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] The impact of Lymphocyte-to-monocyte ratio (LMR) in patients with borderline resectable pancreatic head cancer after curative surgery. (2019)
  • Author(s): Yoji Miyahara, Shigetsugu Takano, Hideyuki Yoshitomi, Shingo Kagawa, Katsunori Furukawa, 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