Suppression of oncogenic signaling by tumor suppressor REIC/Dkk-3

• Project/Area Number: 26293352
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Okayama University
• Principal Investigator: Kumon Hiromi 岡山大学, 医歯(薬)学総合研究科, 特命教授 (30144760)
• Co-Investigator(Kenkyū-buntansha): 高本 篤 岡山大学, 大学病院, 助教 (30716816) ; 江原 伸 岡山大学, 大学病院, 講師 (70379741) ; 阪口 政清 岡山大学, 医歯(薬)学総合研究科, 准教授 (70379840) ; 佐々木 克己 岡山大学, 大学病院, 助教 (80467745)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 遺伝子治療 / 癌増殖抑制 / REIC/Dkk-3 / 遺伝子 / 癌 / バイオテクノロジー / 臨床 / Wnt

Outline of Final Research Achievements

Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor suppressor gene and has been studied with respect to the application of cancer gene therapy. Our previous studies demonstrated that adenovirus-mediated REIC/Dkk-3 overexpression induced significant apoptosis in the treated tumor sites. In this study, we further investigated the mechanisms underlying the antitumor therapeutic effects of Ad-REIC and clarified that the treatment inhibits cancer progression via modification of several oncogenic signaling.

Research Products

• [Journal Article] Expression analysis of Dickkopf-related protein 3 (Dkk3) suggests its pleiotropic roles for a secretory glycoprotein in adult mouse. (2017)
  • Author(s): Inoue J, Fujita H, Bando T, Kondo Y, Kumon H, Ohuchi H
  • Journal Title: J Mol Histol Volume: 48 Issue: 1 Pages: 29-39
  • DOI: 10.1007/s10735-016-9703-2
  • Peer Reviewed / Open Access
• [Journal Article] Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. (2017)
  • Author(s): Suzawa K, Shien K, Peng H, Sakaguchi M, Watanabe M, Hashida S, Maki Y, Yamamoto H, Tomida S, Soh J, Asano H, Tsukuda K, Nasu Y, Kumon H, Miyoshi S, Toyooka S.
  • Journal Title: Anticancer Res Volume: 37 Issue: 1 Pages: 301-307
  • DOI: 10.21873/anticanres.11321
  • Peer Reviewed
• [Journal Article] Promising therapeutic efficacy of a novel REIC/Dkk-3 expressing adenoviral vector for hepatocellular carcinoma. (2017)
  • Author(s): Sawahara H, Shiraha H, Uchida D, Kato H, Kato R, Oyama A, Nagahara T, Iwamuro M, Horiguchi S, Tsutsumi K, Mandai M, Mimura T, Wada N, Takeuchi Y, Kuwaki K, Onishi H, Nakamura S, Watanabe M, Sakaguchi M, et al.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 10 Pages: 1769-1777
  • DOI: 10.1111/jgh.13757
  • Peer Reviewed / Open Access
• [Journal Article] Influence of a single-nucleotide polymorphism of the DNA mismatch repair-related gene exonuclease-1 (rs9350) with prostate cancer risk among Chinese people. (2016)
  • Author(s): Zhang Y, Li P, Xu A, Chen J, Ma C, Sakai A, Xie L, Wang L, Na Y, Kaku H, Xu P, Jin Z, Li X, Guo K, Shen H, Zheng S, Kumon H, Liu C, Huang P
  • Journal Title: Tumour Biol Volume: 37 Issue: 5 Pages: 6653-6659
  • DOI: 10.1007/s13277-015-4298-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor suppressor REIC/DKK-3 and co-chaperone SGTA: Their interaction and roles in the androgen sensitivity (2016)
  • Author(s): Ochiai K, Morimatsu M, Kato Y, Ishiguro-Oonuma T, Udagawa C, Rungsuriyawiboon O, Azakami D, Michishita M, Ariyoshi Y, Ueki H, Nasu Y, Kumon H, Watanabe M, Omi T.
  • Journal Title: Oncotarget Volume: 7 Issue: 3 Pages: 3283-3296
  • DOI: 10.18632/oncotarget.6488
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The induction of antigen-specific CTL by in situ Ad-REIC gene therapy. (2016)
  • Author(s): Ariyoshi Y, Watanabe M, Eikawa S, Yamazaki C, Sadahira T, Hirata T, Araki M, Ebara S, Nasu Y, Udono H, Kumon H.
  • Journal Title: Gene Ther. Volume: gt.2016.7 Issue: 5 Pages: 408-414
  • DOI: 10.1038/gt.2016.7
  • Peer Reviewed / Open Access
• [Journal Article] Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer. (2016)
  • Author(s): Xu P, Xu N, Guo K, Xu A, Takenaka F, Matsuura E, Liu C, Kumon H, Huang P
  • Journal Title: Oncotarget Volume: 7 Issue: 22 Pages: 33025-3334
  • DOI: 10.18632/oncotarget.8846
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. (2016)
  • Author(s): Sawahara H, Shiraha H, Uchida D, Kato H, Nagahara T, Iwamuro M, Kataoka J, Horiguchi S, Watanabe M, Sakaguchi M, Takaki A, Nouso K, Nasu Y, Kumon H, Okada H
  • Journal Title: Cancer Gene Ther Volume: 23 Issue: 8 Pages: 278-283
  • DOI: 10.1038/cgt.2016.31
  • Peer Reviewed
• [Journal Article] Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. (2016)
  • Author(s): Ohtsuka T, Sakaguchi M, Yamamoto H, Tomida S, Takata K, Shien K, Hashida S, Miyata-Takata T, Watanabe M, Suzawa K, Soh J, Youyi C, Sato H, Namba K, Torigoe H, Tsukuda K, Yoshino T, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 33319-33319
  • DOI: 10.1038/srep33319
  • Peer Reviewed / Open Access
• [Journal Article] Adenovirus vector carrying REIC/DKK-3 gene: neoadjuvant intraprostatic injec- tion for high-risk localized prostate cancer undergoing radical prostatectomy. (2016)
  • Author(s): Kumon H, Ariyoshi Y, Sasaki K, Sadahira T, Araki M, Ebara S, Yanai H, Watanabe M, Nasu Y
  • Journal Title: Cancer Gene Ther Volume: 23 Issue: 11 Pages: 400-409
  • DOI: 10.1038/cgt.2016.53
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products, RAGE. (2016)
  • Author(s): Ichiki T, Koga T, Okuno T, Saeki K, Yamamoto Y, Yamamoto H, Sakaguchi M, Yokomizo T
  • Journal Title: FASEB J Volume: 30 Issue: 5 Pages: 1811-1822
  • DOI: 10.1096/fj.201500117
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. (2016)
  • Author(s): Ohtsuka T, Sakaguchi M, Yamamoto H, Tomida S, Takata K, Shien K, Hashida S, Miyata-Takata T, Watanabe M, Suzawa K, Soh J, Youyi C, Sato H, Namba K, Torigoe H, Tsukuda K, Yoshino T, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 39557-39557
  • DOI: 10.1038/srep39557
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations (2016)
  • Author(s): Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda and Shinichiro Miyoshi
  • Journal Title: Cancer Science Volume: 107 Issue: 1 Pages: 45-52
  • DOI: 10.1111/cas.12845
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. (2015)
  • Author(s): Kinoshita R, Watanabe M, Huang P, Li SA, Sakaguchi M, Kumon H, Futami J.
  • Journal Title: Oncology Reports Volume: In press Issue: 6 Pages: 2908-2914
  • DOI: 10.3892/or.2015.3885
  • Peer Reviewed
• [Journal Article] Synergistic anti-pancreatic cancer immunological effects by treatment with REIC/DKK3 protein and peripheral blood mononuclear cells. (2015)
  • Author(s): Uchida D, Shiraha H, Kato H, Sawahara H, Nagahara T, Iwamuro M, Kataoka J, Horiguchi S, Watanabe M, Takaki A, Nouso K, Nasu Y, Kumon H, Yamamoto K
  • Journal Title: J Gastroenterol Hepatol Volume: - Issue: 6 Pages: 1154-1159
  • DOI: 10.1111/jgh.13259
  • Peer Reviewed / Open Access
• [Journal Article] Feasibility of Neoadjuvant Ad-REIC Gene Therapy in Patients with High-Risk Localized Prostate Cancer Undergoing Radical Prostatectomy. (2015)
  • Author(s): Kumon H, Sasaki K, Ariyoshi Y, Sadahira T, Araki M, Ebara S, Yanai H, Watanabe M, Nasu Y
  • Journal Title: Clin Transl Sci Volume: 8 Issue: 6 Pages: 837-840
  • DOI: 10.1111/cts.12362
  • Peer Reviewed / Open Access
• [Journal Article] Ad-REIC Gene Therapy: Promising Results in a Patient with Metastatic CRPC Following Chemotherapy. (2015)
  • Author(s): Hiromi Kumon, Katsumi Sasaki, Yuichi Ariyoshi, Takuya Sadahira, Shin Ebara, Takao Hiraki, Susumu Kanazawa, Hiroyuki Yanai, Masami Watanabe and Yasutomo Nasu.
  • Journal Title: Clinical Medicine Insights: Oncology Volume: 9 Pages: 31-38
  • Peer Reviewed
• [Journal Article] Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. (2014)
  • Author(s): Shimazu Y, Kurozumi K, Ichikawa T, Fujii K, Onishi M, Ishida J, Oka T, Watanabe M, Nasu Y, Kumon H, Date I.
  • Journal Title: Gene Ther Volume: 22 Issue: 2 Pages: 146-154
  • DOI: 10.1038/gt.2014.100
  • Peer Reviewed
• [Journal Article] Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer. (2014)
  • Author(s): Uchida D, Shiraha H, Kato H, Nagahara T, Iwamuro M, Kataoka J, Horiguchi S, Watanabe M, Takaki A, Nouso K, Nasu Y, Yagi T, Kumon H, Yamamoto K.
  • Journal Title: J Gastroenterol Hepatol Volume: 29 Issue: 5 Pages: 973-983
  • DOI: 10.1111/jgh.12501
  • Peer Reviewed
• [Presentation] Adenovirus vector carrying REIC/DKK-3 Gene (Ad-REIC): A new class of therapeutic cancer vaccines (2016)
  • Author(s): Hiromi Kumon
  • Organizer: International Society for Cell & Gene Therapy of Cancer (ISCGT)
  • Place of Presentation: Seoul, Korea
  • Int'l Joint Research / Invited
• [Presentation] New Horizons of Ad-REIC Gene Therapy (2015)
  • Author(s): Hiromi Kumon
  • Organizer: The 4th Symposium of East Asian Gene Therapy Innovative Group－Gene Therapy in East Asia－
  • Place of Presentation: Okayama Plaza Hotel
  • Year and Date: 2015-06-21
  • Int'l Joint Research
• [Presentation] Ad-REIC Gene Therapy for Prostate Cancer (2015)
  • Author(s): Hiromi Kumon
  • Organizer: The 4th International Forum on Frontiers in Urology (IFFU)
  • Place of Presentation: Beijing International Hotel
  • Year and Date: 2015-04-25
  • Int'l Joint Research / Invited
• [Book] 『次世代がん治療』1節担当 固形がんに対するREIC遺伝子組み込みアデノウイルス(Ad-REIC)製剤の開発 (2017)
  • Author(s): 公文 裕巳
  • Publisher: 株式会社 エヌ・ティー・エス