Functional and clinical analysis of angiogenic factor apelin in hepatocellular carcinoma

• Project/Area Number: 24592005
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: SUGIMACHI Keishi 九州大学, 大学病院, 特別教員 (90452763)
• Co-Investigator(Kenkyū-buntansha): SHIRABE Ken 九州大学, 医学(系)研究科(研究院), 准教授 (70264025) ; MAEHARA Yoshihiko 九州大学, 医学(系)研究科(研究院), 教授 (80165662) ; EGUCHI Hidetoshi 九州大学, 大学病院, 講師 (90527756) ; IGUCHI Tomohiro 九州大学, 大学病院, 助教 (30598959) ; AKIYOSHI Sayuri 九州大学, 大学病院, 助教 (50567360) ; SUDO Tomoya 九州大学, 大学病院, 助教 (50309803)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝細胞癌 / 血管新生 / アペリン / F13A / CD34 / アペリンーAPJ / 血管新生阻害 / 分子標的治療

Outline of Final Research Achievements

The aim of this study was to clarify the role of the apelin-APJ system which regulates angiogenesis in tumor progression of hepatocellular carcinoma (HCC). Expressions of angiogenic factors and vascular markers were investigated in specimens from 90 HCC patients. A subcutaneous HCC tumor mouse model was treated with the APJ antagonist, F13A, and tumor growth and vascular development were assessed. APJ expression was observed in arteriole-smooth muscle. Higher amounts of APJ+-arteriole and apelin were detected in tumors (p<0.001 for both). APJ+-arteriole and apelin expression were more commonly observed in moderately- and poorly-differentiated than in well-differentiated HCC (p=0.003). HCC with irregular dilated arteries expressed higher levels of apelin (p=0.012). Tumor growth was inhibited by treatment with F13A (p<0.001), and arterioles were decreased in the treated group (p=0.047), in vivo. Apelin-APJ is overexpressed, and works as a signal for arteriogenesis in HCC.

Research Products

• [Journal Article] A long noncoding RNA, lncRNA-ATB, is involved in the progression and prognosis of colorectal cancer. (2015)
  • Author(s): Iguchi T, Uchi R, Nambara S, Saito T, Komatsu H, Hirata H, Ueda M, Sakimura S, Takano Y, Kurashige J, Shinden Y, Eguchi H, Sugimachi K, Maehara Y, Mimori K.
  • Journal Title: Anticancer Res. Volume: 35 Pages: 1385-8
  • Peer Reviewed
• [Journal Article] The miR-506-Induced Epithelial-Mesenchymal Transition is Involved in Poor Prognosis for Patients with Gastric Cancer. (2015)
  • Author(s): Sakimura S, Sugimachi K, Kurashige J, Ueda M, Hirata H, Nambara S, Komatsu H, Saito T, Takano Y, Uchi R, Sakimura E, Shinden Y, Iguchi T, Eguchi H, Oba Y, Hoka S, Mimori K.
  • Journal Title: Ann Surg Oncol. Volume: epub Issue: S3 Pages: 1436-1443
  • DOI: 10.1245/s10434-015-4418-2
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic modulation and repression of miR-200b by cancer-associated fibroblasts contribute to cancer invasion and peritoneal dissemination in gastric cancer. (2015)
  • Author(s): Kurashige J, Mima K, Sawada G, Takahashi Y, Eguchi H, Sugimachi K, Mori M, Yanagihara K, Yashiro M, Hirakawa K, Baba H, Mimori K.
  • Journal Title: Carcinogenesis. Volume: 36 Issue: 1 Pages: 133-41
  • DOI: 10.1093/carcin/bgu232
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma. (2014)
  • Author(s): Hirata H, Sugimachi K, Takahashi Y, Ueda M, Sakimura S, Uchi R, Kurashige J, Takano Y, Nanbara S, Komatsu H, Saito T, Shinden Y, Iguchi T, Eguchi H, Atsumi K, Sakamoto K, Doi T, Hirakawa M, Honda H, Mimori K.
  • Journal Title: Ann Surg Oncol. Volume: epub Issue: S3 Pages: 1402-9
  • DOI: 10.1245/s10434-014-4242-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic significance of high mobility group box 1 (HMGB1) expression in patients with colorectal cancer. (2014)
  • Author(s): Ueda M, Takahashi Y, Shinden Y, Sakimura S, Hirata H, Uchi R, Takano Y, Kurashige J, Iguchi T, Eguchi H, Sugimachi K, Yamamoto H, Doki Y, Mori M, Mimori K.
  • Journal Title: Anticancer Res. Volume: 34 Pages: 5357-62
  • Peer Reviewed
• [Journal Article] Clinical significance of GAB2, a scaffolding/docking protein acting downstream of EGFR in human colorectal cancer. (2014)
  • Author(s): Matsumura T, Sugimachi K, Takahashi Y, Uchi R, Sawada G, Ueda M, Hirata H, Sakimura S, Ueo H, Takano Y, Kurashige J, Shinden Y, Eguchi H, Sudo T, Yamamoto H, Doki Y, Mori M, Mimori K.
  • Journal Title: Ann Surg Oncol. Volume: 4 Issue: S4 Pages: 743-749
  • DOI: 10.1245/s10434-014-3889-x
  • Peer Reviewed / Open Access
• [Journal Article] Loss of CDCP1 expression promotes invasiveness and poor prognosis in esophageal squamous cell carcinoma. (2014)
  • Author(s): Sawada G, Takahashi Y, Niida A, Shimamura T, Kurashige J, Matsumura T, Ueo H, Uchi R, Takano Y, Ueda M, Hirata H, Sakimura S, Shinden Y, Eguchi H, Sudo T, Sugimachi K, Miyano S, Doki Y, Mori M, Mimori K.
  • Journal Title: Ann Surg Oncol. Volume: 4 Issue: S4 Pages: 640-647
  • DOI: 10.1245/s10434-014-3740-4
  • Peer Reviewed / Open Access
• [Journal Article] Review of angiogenesis in hepatocellular carcinoma. (2014)
  • Author(s): Muto J, Shirabe K, Sugimachi K, Maehara Y.
  • Journal Title: Hepatol Res. Volume: in press Issue: 1 Pages: 1-9
  • DOI: 10.1111/hepr.12310
  • Peer Reviewed
• [Presentation] The role of Plastin3 on the acquisition of cancer stemness and liver metastasis in colorectal camcer (2014)
  • Author(s): 杉町圭史、横堀武彦、井口友宏、江口英利、前原喜彦、三森功士
  • Organizer: 第25回日本消化器癌発生学会
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-13 – 2014-11-14
• [Presentation] 肝細胞癌におけるＰＲＲＸ１の発現異常とがん幹細胞性・治療抵抗性獲得に関する検討 (2014)
  • Author(s): 平田秀成、杉町圭史、内龍太郎、藏重淳二,上田正射、崎村正太郎、新田吉陽、江口英利、平川雅和、本田浩、三森功士
  • Organizer: 第52回日本癌治療学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-08-28 – 2014-08-30
• [Presentation] 肝細胞癌の再発を予測する新規血中バイオマーカーの探索ー血液中エクソソーム内マイクロＲＮＡの同定とその機序解析ー (2014)
  • Author(s): 杉町圭史、松村多恵、平田秀成、内龍太郎、新田吉陽、江口英利、主藤朝也、調憲、前原喜彦、三森功士
  • Organizer: 第69回日本消化器外科学会総会
  • Place of Presentation: 郡山
  • Year and Date: 2014-07-16
• [Presentation] 術前の超選択的なTACE・PVE併用によって安全に根治切除可能であった巨大肝細胞癌の1例 (2014)
  • Author(s): 杉町圭史、江口英利、松村多恵、三森功士
  • Organizer: 第26回日本肝胆膵外科学会学術集会
  • Place of Presentation: 和歌山
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] 肝細胞癌における血管新生因子としてのapelin/APJ系の意義 (2013)
  • Author(s): 武藤 純, 調 憲, 吉屋 匠平, 的野 る美, 戸島 剛男, 播本 憲史, 池上 徹, 山下 洋一, 内山 秀昭, 吉住 朋晴, 副島 雄二, 前原 喜彦
  • Organizer: 第113回日本外科学会総会
  • Place of Presentation: 福岡市
• [Presentation] 肝細胞癌の血管新生におけるapelin/APJ系の意義 (2012)
  • Author(s): 武藤 純、池上 徹、吉住朋晴、調 憲、 前原喜彦ら
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張
• [Presentation] 肝細胞癌の新しい血管新生阻害療法の可能性 apelin/APJ系に注目して (2012)
  • Author(s): 武藤 純、池上 徹、吉住朋晴、調 憲、 前原喜彦ら
  • Organizer: JDDW 2012
  • Place of Presentation: 神戸