The expandion in application of novel treatment through the liver specific siginaling pathway for the intractable and advanced hepatocellular carcinoma

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390378
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: NAGANO Hiroaki 大阪大学, 医学系・研究科, 准教授 (10294050)
• Co-Investigator(Kenkyū-buntansha): MARUBASHI Sigeru 大阪大学, 医学系・研究科, 助教 (20362725) ; KOBAYASHI Shougo 大阪大学, 医学系・研究科, 助教 (30452436) ; TAKEMASA Ichiro 大阪大学, 医学系・研究科, 助教 (50379252)
• Project Period (FY): 2009 – 2011
• Keywords: 肝細胞癌 / 難治性進行癌 / 門脈内腫瘍栓 / インターフェロン / 化学療法 / インターフェロン受容体 / 血管新生 / トランスクリプトーム解析

Research Abstract

SUMMARY OF RESEARCH RESULTS
(1) The mechanism of the antitumor effect through the IFN-IFNAR signaling
The anti-tumor effect of IFN/ 5-FU combined therapy was significantly correlated with the strength of IFNAR expression, in the HCC cells in-vitro. This was also proved in the experiment of the IFNAR gene transfection model. In this mechanism, the upragulation of the p-STATS and Bcl-xl expression were most significantly correlated with anti-tumor effect, among the several signal transductional factors.
(2) Anti tumor effect through TRAIL/ TRAIL receptor and Fas/ FasL
Among peripheral blood cells, NK cells were found to exert the cytotoxic effects on human hepatoma cells. In addition, the involvement of CTL system in the anti tumor effect was examined and confirmed in terms of the relationship of apoptosis in this study.
(3) The Gene Expression Profiling
Using the clinical samples treated by IFN-αand 5-FU, the gene expression profiling would be suggested to be useful for the prediction of the treatment efficacy. In addition, the 2 candidates of predictive factors for anti-tumor effect of IFN-αand 5-FU was identified by Gene Expression Profiling with unresponsive HCC cell lines.

Research Products

• [Journal Article] Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice (2011)
  • Author(s): Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Tsunematsu H, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Kanto T, Hiramatsu N, Kubota S, Takigawa M, Tomimaru Y, Tomokuni A, Nagano H, Doki Y, Mori M, Hayashi N
  • Journal Title: J Clin Invest Volume: 121(8) Pages: 3343-3356
  • Peer Reviewed
• [Journal Article] miR-146a suppresses the sensitivity to interferon-<alpha> in hepatocellular carcinoma cells (2011)
  • Author(s): Tomokuni, A, Eguchi H ; Tomimaru Y, Wada H, Kawamoto K, Kobayashi S, Marubashi S, Tanemura M, Nagano H, Mori M, Doki Y
  • Journal Title: BBRC 2011 Volume: 414(4) Pages: 675-68
  • Peer Reviewed
• [Journal Article] Advantage of autologous blood transfusion in surgery for hepatocellular carcinoma (2011)
  • Author(s): Tomimaru Y, Eguchi H, Marubashi S, Wada H, Kobayashi S, Tanemura M, Umeshita K, Doki Y, Mori M, Nagano H
  • Journal Title: World J Gastroenterol Volume: 17(32) Pages: 3709-3715
  • Peer Reviewed
• [Journal Article] Clinical significance of alpha-fetoprotein mRNA in peripheral blood in liver resection for hepatocellular carcinoma (2011)
  • Author(s): Marubashi S, Nagano H, Wada H, Kobayashi S, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M
  • Journal Title: Ann Surg Oncol Volume: 18(8) Pages: 2200-2209
  • Peer Reviewed
• [Journal Article] Long-term outcome of combined subcutaneous interferon-τand intra-arterial 5-fluorouracil treatment for advanced hepatocellular carcinoma with major portal vein thrombosis (2011)
  • Author(s): Nagano H, Wada H, Kobayashi S, Marubashi S, Eguchi H, Tanemura M, Tomimaru Y, Osuga K, Umeshita K, Doki Y, Mori M
  • Journal Title: Oncology 2011 Volume: 80(1-2) Pages: 63-69
  • Peer Reviewed
• [Journal Article] Prognosis of hepatocellular carcinoma with biliary tumor thrombi following liver surgery (2011)
  • Author(s): Noda T, Nagano H, Tomimaru Y, Murakami M, Wada H, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Kim T, Wakasa K, Doki Y, Mori M
  • Journal Title: Surgery Volume: 149(3) Pages: 371-377
  • Peer Reviewed
• [Journal Article] Tyrosine kinase inhibitor PTK/ ZK enhances the anti-tumor effects of interferon-α/ 5-fluorouracil therapy for hepatocellular carcinoma cells (2011)
  • Author(s): Murakami M, Kobayashi S, Marubashi S, Tomimaru Y, Noda T, Wada H, Eguchi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M, Nagano H
  • Journal Title: Ann Surg Oncol Volume: 18(2) Pages: 589-596
  • Peer Reviewed
• [Journal Article] 進行肝癌に対する集学的治療 (2011)
  • Author(s): 永野浩昭、和田浩志、丸橋繁、川本弘一、小林省吾、江口英利、種村匡弘、土岐祐一郎、森正樹
  • Journal Title: 外科治療 Volume: 105(5) Pages: 461-466
  • Peer Reviewed
• [Journal Article] MicroRNA-21 induces resistance to the anti-tumor effect of interferon-α/ 5-fluorouracil in hepatocellular carcinoma cells (2010)
  • Author(s): Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A, Kobayashi S, Marubashi S, Tanemura M, Takeda Y, Umeshita K, Doki Y, Mori M
  • Journal Title: Br J Cancer Volume: 103(10) Pages: 1617-1626
  • Peer Reviewed
• [Journal Article] Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma : correlation with histological grading and portal blood flow (2010)
  • Author(s): Kogita S, Imai Y, Okada M, Kim T, Onishi H, Takamura M, Fukuda K, Igura T, Sawai Y, Morimoto O, Hori M, Nagano H, Wakasa K, Hayashi N, Murakami T
  • Journal Title: Eur Radiol Volume: 20(10) Pages: 2405-2413
  • Peer Reviewed
• [Journal Article] Exploration of Potential Genomic Portraits Associated with Intrahepatic Recurrence in Human Hepatocellular Carcinoma (2010)
  • Author(s): Kittaka N, , Seno S, Takeda Y, Kobayashi S, Marubashi S, Dono K, Umeshita K, Nagano H, Matsuda H, Monden M, Mori M, Doki Y
  • Journal Title: Ann Surg Oncol Volume: 17(12) Pages: 3145-3154
  • Peer Reviewed
• [Journal Article] Treatment of advanced hepatocellular carcinoma : intraarterial infusion chemotherapy combined with interferon (2010)
  • Author(s): Nagano H
  • Journal Title: Oncology Volume: 78(suppl1) Pages: 142-147
  • Peer Reviewed
• [Journal Article] Effects of preceding interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma (2010)
  • Author(s): Tomimaru Y, Nagano H, Eguchi H, Kobayashi S, Marubashi S, Wada H, Tanemura M, Umeshita K, Hiramatsu H, Takehara T, Doki Y, Mori M
  • Journal Title: J of Surg Oncol Volume: 102 Pages: 308-314
  • Peer Reviewed
• [Journal Article] Insulin-Like Growth Factor-Binding Protein 7 Alters the Sensitivity to Interferon-Based Anticancer Therapy in Hepatocellular Carcinoma Cells (2010)
  • Author(s): Tomimaru Y, Eguchi H, Wada H, Noda H, Murakami M, Kobayashi S, Marubashi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M, Nagano H
  • Journal Title: B J Cancer Volume: 102(10) Pages: 1483-1490
  • Peer Reviewed
• [Journal Article] The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma (2010)
  • Author(s): Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, Tatsumi T, Ishida H, Noda T, Nagano H, Doki Y, Mori M, Hayashi N
  • Journal Title: J Hepatol Volume: 52(5) Pages: 698-704
  • Peer Reviewed
• [Journal Article] Hepatocellular carcinoma : hepatocyte-selective enhancement at gadoxetic acid-enhanced MRImaging-correlation with expression of sinusoidal and canalicular transporters and bile accumulation (2010)
  • Author(s): Tsuboyama T, Onishi H, Kim T, Akita H, Hori M, Tatsumi M, Nakamoto A, Nagano H, Matsuura N, Wakasa K, Tomoda K
  • Journal Title: Radiology Volume: 255(3) Pages: 824-833
  • Peer Reviewed
• [Journal Article] Isolated Metastasis to the Gall Bladder from Hepatocellular Carcinoma (2010)
  • Author(s): Murakami M, Kobayashi S, Marubashi S, Eguchi S, Takeda Y, Tanemura M, Wada H, Umeshita K, , Wakasa K, Doki Y, Mori M, Nagano H
  • Journal Title: Hepatology Research Volume: 40(8) Pages: 793-798
  • Peer Reviewed
• [Journal Article] Effects of preoperative transcatheter arterial chemoembolization for resectable hepatocellular carcinoma : Implication of circulating cancer cells by detection of alpha-fetoprotein mRNA (2010)
  • Author(s): Murakami M, Nagano H, Kobayashi S, Nakamura M, Marubashi S, Eguchi H, Takeda Y, Tanemura M, Sugita Y, Umeshita K, Monden M, Doki Y, Mori M
  • Journal Title: Experimental and Therapeutic Medicine Volume: 1 Pages: 485-491
  • Peer Reviewed
• [Journal Article] Molecular prediction of early recurrence after resection of hepatocellular carcinoma (2009)
  • Author(s): Yoshioka S, Takemasa I, Nagano H, Kittaka N, Noda T, Wada H, Kobayashi S, Marubashi S, Takeda Y, Umeshita K, Dono K, Matsubara K, Matsubara N, Monden M
  • Journal Title: EJ Cancer Volume: 45(5) Pages: 881-889
  • Peer Reviewed
• [Journal Article] Activation of Wnt/ beta-catenin signalling pathway induces chemoresistance to interferon-alpha/ 5-fluorouracil combination therapy for hepatocellular carcinoma (2009)
  • Author(s): Noda T, Nagano H, Takemasa I, Yoshioka S, Murakami M, Wada H, Kobayashi S, Marubashi S, Takeda Y, Dono K, Umeshita K, Matsuura N, Matsubara K, Doki Y, Mori M, Monden M
  • Journal Title: Br J Cancer Volume: 100(10) Pages: 1647-1658
  • Peer Reviewed
• [Journal Article] A safe protocol of intermittent hilar vascular clamping for hepatic resection in cirrhosis (2009)
  • Author(s): Nagano H, Miyamoto A, Kishimoto S, Takeda Y, Marubashi S, Kobayashi S, Tomimaru Y, Noda T, Umeshita K, Dono K, SakonM, Monden M
  • Journal Title: Hepatogastroenterol Volume: 88(9) Pages: 1123-1130
  • Peer Reviewed
• [Journal Article] Combination of interferon-alpha and 5-fluorouracil inhibits endothelial cell growth through regulation of angiogenic factors released by tumor cells (2009)
  • Author(s): Wada H, Nagano H, Yamamoto H, Noda T, Murakami M, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Doki Y and Mori M
  • Journal Title: BMC Cancer Volume: 9 Pages: 361-372
  • Peer Reviewed
• [Journal Article] 癌幹細胞と薬剤耐性 (2009)
  • Author(s): 永野浩昭、石井秀始、土岐祐一郎、森正樹
  • Journal Title: Cancer Frontier Volume: 11 Pages: 100-105
  • Peer Reviewed
• [Presentation] 肝癌に対する外科治療 (2011)
  • Author(s): 永野浩昭、土岐祐一郎、森正樹
  • Organizer: 第28回日本医学会総会
  • Place of Presentation: (東京)[シンポジウム]
  • Year and Date: 2011-04-08
• [Presentation] 肝細胞癌術後再発への治療戦略-長期予後を目指して- (2010)
  • Author(s): 永野浩昭、丸橋繁、小林省吾、和田浩志、江口英利、武田裕、種村匡弘、梅下浩司、門田守人、土岐祐一郎、森正樹
  • Organizer: 第65回日本消化器外科学会総会
  • Place of Presentation: (下関)[シンポジウム]
  • Year and Date: 2010-07-14
• [Presentation] 脈管侵襲陽性・進行肝細胞癌に対する集学的治療 (2009)
  • Author(s): 永野浩昭、丸橋繁、武田裕、小林省吾、種村匡弘、堂野恵三、梅下浩司、門田守人、土岐祐一郎、森正樹
  • Organizer: 第64回日本消化器外科学会総会
  • Place of Presentation: (大阪)[シンポジウム]
  • Year and Date: 2009-07-16
• [Presentation] 肝細胞癌に対する成人間生体肝移植における再発予測に関する検討 (2009)
  • Author(s): 永野浩昭、丸橋繁、小林省吾、江口英利、武田裕、種村匡弘、梅下浩司、門田守人、土岐祐一郎、森正樹
  • Organizer: 第27回日本肝移植研究会
  • Place of Presentation: (三島)[シンポジウム]
  • Year and Date: 2009-07-10
• [Presentation] 肝細胞癌切除後10年無再発症例の検討 (2009)
  • Author(s): 永野浩昭、丸橋繁、野田剛広、小林省吾、江口英利、武田裕、種村匡弘、梅下浩司、若狭研一、門田守人、土岐祐一郎、森正樹
  • Organizer: 第45回日本肝癌研究会
  • Place of Presentation: (福岡)[シンポジウム]
  • Year and Date: 2009-07-03
• [Presentation] 血行再建を伴う進行肝細胞癌に対する肝切除 (2009)
  • Author(s): 永野浩昭、丸橋繁、武田裕、小林省吾、種村匡弘、北川透、梅下浩司、堂野恵三、門田守人、土岐祐一郎、森正樹
  • Organizer: 第21回日本肝胆膵外科学会
  • Place of Presentation: (名古屋)[ビデオシンポジウム]
  • Year and Date: 2009-06-10
• [Presentation] 肝癌外科治療後の再発予測・予防における臨床・基礎両面からの個別化医療への可能性 (2009)
  • Author(s): 永野浩昭、丸橋繁、竹政伊知朗、小林省吾、武田裕、種村匡弘、北川透、堂野恵三、土岐祐一郎、森正樹、門田守人
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: (神戸)[ワークショップ]
  • Year and Date: 2009-06-04
• [Presentation] Treatment of Advanced HCC with macrovascular invasion and no extrahepatic spread : Beneficial effect of combination therapy of IFN/ 5-FU for advanced HCC with PVTT (2009)
  • Author(s): 永野浩昭、土岐祐一郎、森正樹
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: (神戸)[シンポジウム]
  • Year and Date: 2009-06-04
• [Presentation] 門脈内腫瘍栓をともなう進行肝細胞癌におけるIFN併用化学療法の位置づけ (2009)
  • Author(s): 永野浩昭、門田守人、森正樹
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: (札幌)[シンポジウム]
  • Year and Date: 2009-05-07
• [Book] 消化器疾患診療の課題と展望 (2011)
  • Author(s): 永野浩昭、森正樹
  • Total Pages: 27-29
  • Publisher: 先端医療技術研究所、東京