TSP-1 expression of hepatocellular carcinoma in recurrence and metastasis after hepatectomy: the mechanism and therapeutic strategy.

• Project/Area Number: 17K10670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: Kuroki Hideyuki 熊本大学, 病院, 非常勤診療医師 (50594876)
• Co-Investigator(Kenkyū-buntansha): 今井 克憲 熊本大学, 大学院生命科学研究部(医), 助教 (60555746) ; 東 孝暁 熊本大学, 病院, 医員 (70594878) ; 林 洋光 熊本大学, 病院, 助教 (80625773)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肝細胞癌 / Thrombospondin 1 / sorafenib / p38 MAP kinase / SB203580 / 肝切除術 / 肝再生 / TSP-1 / HCC / Hepatectomy / TGF-β / Sorafenib / LSKL peptide

Outline of Final Research Achievements

TSP-1 was induced in the early phase after hepatectomy and regulated lever regeneration. The role of TSP-1 in HCC progression has not well been known.
We investigated TSP-1 expression in HCC cell line and categorized to high TSP-1 cell and low TSP-1 cell. Sorafenib, multi-kinase inhibitor, strongly regulated proliferation of high TSP-1 expression cell. SB203580 which is inhibitor of p38 MAP kinase locating at upstream of TSP-1, attenuated tumor regulation effect by sorafenib. TSP-1 inhibition promotes remnant liver regeneration after hepatectomy and regulate proliferation of cancer cell for TSP-1 high expression HCC.

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌（HCC）に対する根治的治療は現在のところ外科的肝切除が最も治療効果が期待できる。術後は早期より肝再生が誘導されることが術後の良好な経過に繋がる。術後に誘導されるTSP-1が肝再生を抑制しており、TSP-1を抑制すれば残肝再生を促進できるが、肝細胞癌におけるTSP-1の機能については不明な点が多い。本研究ではTSP-1高発現のHCCに対して、TSP-1抑制は肝切除後の肝再生を促進すると共に、抗腫瘍効果を期待できることが示唆される。

Research Products

• [Journal Article] Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma (2019)
  • Author(s): Umezaki Naoki、Nakagawa Shigeki、Yamashita Yo‐ichi、Kitano Yuki、Arima Kota、Miyata Tatsunori、Hiyoshi Yukiharu、Okabe Hirohisa、Nitta Hidetoshi、Hayashi Hiromitsu、Imai Katsunori、Chikamoto Akira、Baba Hideo
  • Journal Title: Cancer Science Volume: 110(6) Issue: 6 Pages: 2033-2043
  • DOI: 10.1111/cas.14010
  • Peer Reviewed / Open Access
• [Journal Article] Is disease progression a contraindication for the strategy of portal vein embolization followed by hepatectomy for hepatocellular carcinoma? (2019)
  • Author(s): Imai Katsunori、Yamashita Yo-ichi、Nakao Yosuke、Uemura Norio、Kitamura Fumimasa、Miyata Tatsunori、Nakagawa Shigeki、Okabe Hirohisa、Hayashi Hiromitsu、Chikamoto Akira、Ishiko Takatoshi、Baba Hideo
  • Journal Title: Surgery Volume: 165 Issue: 4 Pages: 696-702
  • DOI: 10.1016/j.surg.2018.10.023
  • Peer Reviewed
• [Journal Article] Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma (2018)
  • Author(s): Nakagawa Shigeki、Okabe Hirohisa、Ouchi Mayuko、Tokunaga Ryuma、Umezaki Naoki、Higashi Takaaki、Kaida Takatoshi、Arima Kota、Kitano Yuki、Kuroki Hideyuki、Mima Kosuke、Nitta Hidetoshi、Imai Katsunori、Hashimoto Daisuke、Yamashita Yo-ichi、Chikamoto Akira、Baba Hideo
  • Journal Title: HPB Volume: 20 Issue: 10 Pages: 939-948
  • DOI: 10.1016/j.hpb.2018.03.018
  • Peer Reviewed
• [Journal Article] Histological architectural classification determines recurrence pattern and prognosis after curative hepatectomy in patients with hepatocellular carcinoma (2018)
  • Author(s): Okabe Hirohisa、Yoshizumi Tomoharu、Yamashita Yo-ichi、Imai Katsunori、Hayashi Hiromitsu、Nakagawa Shigeki、Itoh Shinji、Harimoto Norifumi、Ikegami Toru、Uchiyama Hideaki、Beppu Toru、Aishima Shinichi、Shirabe Ken、Baba Hideo、Maehara Yoshihiko
  • Journal Title: PLOS ONE Volume: 13 Issue: 9 Pages: e0203856-e0203856
  • DOI: 10.1371/journal.pone.0203856
  • Peer Reviewed
• [Journal Article] Predicting Poorly Differentiated Hepatocellular Carcinoma that Meets the Milan Criteria (2018)
  • Author(s): KOGA YUKI、BEPPU TORU、MIYATA TATSUNORI、KITANO YUKI、TSUJI AKIRA、NAKAGAWA SHIGEKI、ARIMA KOTA、KURAMOTO KUNITAKA、OKABE HIROHISA、IMAI KATSUNORI、HAYASHI HIROMITSU、NITTA HIDETOSHI、YAMASHITA YO-ICHI、CHIKAMOTO AKIRA、ISHIKO TAKATOSHI、BABA HIDEO
  • Journal Title: Anticancer Research Volume: 38 Issue: 7 Pages: 4093-4099
  • DOI: 10.21873/anticanres.12699
  • Peer Reviewed
• [Journal Article] Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination. (2018)
  • Author(s): Kuramoto K, Beppu T, Nitta H, Imai K, Masuda T, Miyata T, Koga Y, Kitano Y, Kaida T, Nakagawa S, Okabe H, Hayashi H, Hashimoto D, Yamashita YI, Chikamoto A, Kikuchi K, Baba H.
  • Journal Title: Anticancer Res. Volume: 38(1) Pages: 525-531
  • Peer Reviewed
• [Journal Article] Impact of surgical treatment after sorafenib therapy for advanced hepatocellular carcinoma (2018)
  • Author(s): Takeyama Hideaki、Beppu Toru、Higashi Takaaki、Kaida Takayoshi、Arima Kota、Taki Katsunobu、Imai Katsunori、Nitta Hidetoshi、Hayashi Hiromitsu、Nakagawa Shigeki、Okabe Hirohisa、Hashimoto Daisuke、Chikamoto Akira、Ishiko Takatoshi、Tanaka Motohiko、Sasaki Yutaka、Baba Hideo
  • Journal Title: Surgery Today Volume: 48 Issue: 4 Pages: 431-438
  • DOI: 10.1007/s00595-017-1603-x
  • Peer Reviewed
• [Journal Article] Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: is it time to reconsider the current treatment guidelines? (2018)
  • Author(s): Imai Katsunori、Baba Hideo
  • Journal Title: HepatoBiliary Surgery and Nutrition Volume: 7 Issue: 4 Pages: 300-301
  • DOI: 10.21037/hbsn.2018.05.02
  • Peer Reviewed / Open Access
• [Journal Article] Microvascular invasion of single small hepatocellular carcinoma ?3 cm: Predictors and optimal treatments (2018)
  • Author(s): Yamashita Yo-ichi、Imai Katsunori、Yusa Toshihiko、Nakao Yosuke、Kitano Yuki、Nakagawa Shigeki、Okabe Hirohisa、Chikamoto Akira、Ishiko Takatoshi、Yoshizumi Tomoharu、Aishima Shinichi、Maehara Yoshihiko、Baba Hideo
  • Journal Title: Annals of Gastroenterological Surgery Volume: 2 Issue: 3 Pages: 197-203
  • DOI: 10.1002/ags3.12057
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. (2018)
  • Author(s): Miyata T, Yamashita Y, Baba Y, Harada K, Yamao T, Umezaki N, Tsukamoto M, Kitano Y, Yamamura K, Arima K, Nakagawa S, Okabe H, Imai K, Hashimoto D, Chikamoto A, Shimokawa M, Baba H
  • Journal Title: Oncotarget Volume: 9 Issue: 29 Pages: 20795-20806
  • DOI: 10.18632/oncotarget.25124
  • Peer Reviewed / Open Access
• [Journal Article] Significance for Outcomes Following Hepatectomy and Radiofrequency Ablation. (2018)
  • Author(s): Imai K, Yamashita YI, Yusa T, Nakao Y, Itoyama R, Nakagawa S, Okabe H, Chikamoto A, Ishiko T, Baba H.
  • Journal Title: Anticancer Res. Volume: 38(2) Pages: 1053-1060
  • Peer Reviewed
• [Journal Article] Long-term Favorable Outcomes of Radiofrequency Ablation for Hepatocellular Carcinoma as an Initial Treatment: A Single-center Experience Over a 10-Year Period. (2018)
  • Author(s): Tsukamoto M, Yamashita YI, Imai K, Umezaki N, Yamao T, Kaida T, Mima K, Nakagawa S, Hashimoto D, Chikamoto A, Ishiko T, Baba H.
  • Journal Title: Anticancer Res. Volume: 38(2) Pages: 1047-1052
  • Peer Reviewed
• [Journal Article] Surgical treatment strategy for hepatocellular carcinoma in patients with impaired liver function: hepatic resection or radiofrequency ablation? (2018)
  • Author(s): Yamao Takanobu、Imai Katsunori、Yamashita Yo-ichi、Kaida Takayoshi、Nakagawa Shigeki、Mima Kosuke、Hashimoto Daisuke、Chikamoto Akira、Ishiko Takatoshi、Baba Hideo
  • Journal Title: HPB Volume: 20 Issue: 3 Pages: 244-250
  • DOI: 10.1016/j.hpb.2017.08.031
  • Peer Reviewed
• [Journal Article] The predictors and oncological outcomes of repeat surgery for recurrence after hepatectomy for colorectal liver metastases. (2018)
  • Author(s): Imai K, Yamashita YI, Miyamoto Y, Nakagawa S, Okabe H, Hashimoto D, Chikamoto A, Baba H.
  • Journal Title: Int J Clin Oncol. Volume: Apr 4 Issue: 5 Pages: 908-916
  • DOI: 10.1007/s10147-018-1273-8
  • Peer Reviewed
• [Journal Article] Microvascular Invasion in Small-sized Hepatocellular Carcinoma: Significance for Outcomes Following Hepatectomy and Radiofrequency Ablation. (2018)
  • Author(s): Imai K, Yamashita YI, Yusa T, Nakao Y, Itoyama R, Nakagawa S, Okabe H, Chikamoto A, Ishiko T, Baba H.
  • Journal Title: Anticancer Res. Volume: 38(2) Issue: 2 Pages: 1053-1060
  • DOI: 10.21873/anticanres.12322
  • Peer Reviewed
• [Journal Article] Erratum to: Sarcopenia, but not visceral fat amount, is a risk factor of postoperative complications after major hepatectomy. (2017)
  • Author(s): Higashi T, Hayashi H, Taki K, Sakamoto K, Kuroki H, Nitta H, Hashimoto D, Chikamoto A, Beppu T, Baba H.
  • Journal Title: Int J Clin Oncol. Volume: 22(5) Issue: 5 Pages: 986-990
  • DOI: 10.1007/s10147-017-1163-5
  • Peer Reviewed
• [Journal Article] Potential of a cure in patients with colorectal liver metastases and concomitant extrahepatic disease. (2017)
  • Author(s): Imai K, Castro Benitez C, Allard MA, Vibert E, Sa Cunha A, Cherqui D, Castaing D, Bismuth H, Baba H, Adam R
  • Journal Title: J Surg Oncol. Volume: 115(4) Issue: 4 Pages: 488-496
  • DOI: 10.1002/jso.24539
  • Peer Reviewed
• [Journal Article] Impact of Surgical Treatment for Recurrence After 2-Stage Hepatectomy for Colorectal Liver Metastases, on Patient Outcome. (2017)
  • Author(s): Imai K, Benitez CC, Allard MA, Vibert E, Cunha AS, Cherqui D, Castaing D, Bismuth H, Baba H, Adam R.
  • Journal Title: Ann Surg. Volume: Aug 17 Issue: 2 Pages: 322-330
  • DOI: 10.1097/sla.0000000000002472
  • Peer Reviewed
• [Journal Article] Long-term outcomes of radiofrequency ablation combined with hepatectomy compared with hepatectomy alone for colorectal liver metastases. (2017)
  • Author(s): Imai K, Allard MA, Castro Benitez C, Vibert E, Sa Cunha A, Cherqui D, Castaing D, Baba H, Adam R.
  • Journal Title: Br J Surg. Volume: 104(5) Issue: 5 Pages: 570-579
  • DOI: 10.1002/bjs.10447
  • Peer Reviewed
• [Journal Article] Thrombospondin-1 expression may be implicated in liver atrophic mechanism due to obstructed portal venous flow. (2016)
  • Author(s): Hayashi H, Kuroki H, Higashi T, Takeyama H, Yokoyama N, Okabe H, Nitta H, Beppu T, Takamori H, Baba H.
  • Journal Title: Hepatol Res Volume: Epub Issue: 8 Pages: 803-812
  • DOI: 10.1111/hepr.12792
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 肝細胞癌の分子分類と個別化治療への応用 (2019)
  • Author(s): 東 孝暁、松村 和季、清水 健次、小川 克大、新田 英利、増田 稔郎、赤星 慎一、松本 克孝、生田 義明、沖野 哲也、中川 茂樹、星田 有人、馬場 秀夫、高森 啓史
  • Organizer: 第119回 日本外科学会定期学術集会
• [Presentation] 腹腔鏡下再肝切除の問題点とアプローチ法の工夫 (2019)
  • Author(s): 林 洋光、山下 洋市、北村 文優、上村 紀雄、中川 茂樹、岡部 弘尚、今井 克憲、近本 亮、高森 啓史、馬場 秀夫
  • Organizer: 第74回 日本消化器外科学会総会
• [Presentation] 血小板低値である肝細胞癌における肝切除術の安全性の検討 (2019)
  • Author(s): 上村 紀雄、今井 克憲、北村 文優、宮田 辰徳、中川 茂樹、岡部 弘尚、林 洋光、山下 洋市、近本 亮、馬場 秀夫
  • Organizer: 第119回 日本外科学会定期学術集会
• [Presentation] 腹腔鏡下肝後区域切除のコツとピットホール ～定型化へ向けて～ (2018)
  • Author(s): 林 洋光、生田義明、増田稔郎、緒方健一、松本克孝、赤星慎一、小川克大、武山秀晶、山根大侍、高森啓史
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] 高難度肝切除を安全に行うための多角的取り組み (2018)
  • Author(s): 林 洋光、生田義明、赤星慎一、増田稔郎、緒方健一、松本克孝、小川克大、武山秀晶、山根大侍、高森啓史
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 大腸癌両葉多発肝転移に対する積極的な外科治療戦略 (2018)
  • Author(s): 今井克憲、馬場秀夫、Adam Rene
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 高難度肝切除を安全に行うための多角的取り組み (2018)
  • Author(s): 林 洋光、生田 義明、赤星 慎一、増田 稔郎、緒方 健一、松本 克孝、小川 克大、武山 秀晶、山根 大侍、高森 啓史
  • Organizer: 第118回 日本外科学会定期学術集会
• [Presentation] 大腸癌両葉多発肝転移に対する積極的な治療戦略 (2018)
  • Author(s): 今井 克憲、馬場 秀夫、Adam Rene
  • Organizer: 第118回 日本外科学会定期学術集会
• [Presentation] 肝再生および肝萎縮におけるトロンボスポンディン1の役割解明と臨床応用への探索 (2017)
  • Author(s): 林 洋光、黒木 秀幸、東 孝暁:、武山 秀晶、岡部 弘尚、今井 克憲、山下 洋市、高森 啓史、馬場 秀夫
  • Organizer: 第117回 日本外科学会定期学術集会