Elucidate the mechanism of anti-cancer drug resistance caused by inhibitor apoptosis protein(IAP) and development of novel therapeutic strategy

• Project/Area Number: 26861737
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Kumamoto University
• Principal Investigator: NAGATA MASASHI 熊本大学, 医学部附属病院, 非常勤診療医師 (10635791)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 抗がん剤耐性 / アポトーシス / 腫瘍周囲環境

Outline of Final Research Achievements

We have reported the importance of cellular inhibitor of apoptosis 2 (cIAP2) using 5FU-resistant oral squamous cell carcinoma cell line, which we establish for 2 years 5FU treatment. We presented treatment-resistant and poor prognosis was due to cIAP2 high expression. To analyze of cIAP2 regulator, we found relevance of miR-30a overexpression and apoptosis inhibition. In additon, an overexpression of extracellular matrix molecule fibronectin activate of survival regulator and confers cell adhesion-mediated drug resistance against 5-FU. Furthermore, we reported tumour-associated macrophages (TAMs) are a potential biomarker for predicting the clinical response to 5-FU-based chemoradiotherapy, and the expression status of the cancer-associated fibroblasts and TAMs may be useful for making treatment decisions to improve the survival of OSCC patients.

Research Products

• [Journal Article] Pre-treatment neutrophil to lymphocyte ratio predicts the chemoradiotherapy outcome and survival in patients with oral squamous cell carcinoma (2016)
  • Author(s): Hikaru Nakashima, Yuichiro Matsuoka, Ryoji Yoshida, Masashi Nagata, Akiyuki Hirosue, Kenta Kawahara, Jyunki Sakata, Hidetaka Arita, Akimitsu Hiraki and Hideki Nakayama
  • Journal Title: BMC Cancer Volume: 26 Issue: 1 Pages: 41-41
  • DOI: 10.1186/s12885-016-2079-6
  • Peer Reviewed / Open Access
• [Journal Article] The tumour stromal features are associated with resistance to 5-FU-based chemoradiotherapy and a poor prognosis in patients with oral squamous cell carcinoma. (2015)
  • Author(s): Matsuoka Y, Yoshida R, Nakayama H, Nagata M, Hirosue A, Tanaka T, Kawahara K, Nakagawa Y, Sakata J, Arita H, Hiraki A, Shinohara M.
  • Journal Title: APMIS Volume: 3 Issue: 3 Pages: 205-14
  • DOI: 10.1111/apm.12344
  • Peer Reviewed / Open Access
• [Journal Article] Phase II clinical trial of multiple peptide vaccination for advanced head and neck cancer patients revealed induction of immune responses and improved OS (2015)
  • Author(s): Yoshitake, Y., Fukuma, D., Yuno, A., Hirayama, M., Nakayama, H., Tanaka. T., Nagata, M., Takamune, Y., Kawahara, K., Nakagawa, Y., Yoshida, R., Hirosue, A., Ogi, H., Hiraki, A. , Jono, H., Hamada, A., Yoshida, K., Nishimura, Y., Nakamura, Y., Shinohara, M.
  • Journal Title: Clinical Cancer Research Volume: 21 Issue: 2 Pages: 312-321
  • DOI: 10.1158/1078-0432.ccr-14-0202
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The tumour stromal features are associated with resistance to 5-FU-based chemoradiotherapy and a poor prognosis in patients with oral squamous cell carcinoma. (2015)
  • Author(s): Matsuoka Y, Yoshida R, Nakayama H, Nagata M, Hirosue A, Tanaka T, Kawahara K, Nakagawa Y, Sakata J, Arita H, Hiraki A, Shinohara M.
  • Journal Title: acta pathologica, microbiologica, et immunologica Scandinavica Volume: 123 Pages: 205-14
  • Peer Reviewed
• [Journal Article] A low Dicer expression is associated with resistance to 5-FU-based chemoradiotherapy and a shorter overall survival in patients with oral squamous cell carcinoma. (2014)
  • Author(s): Kawahara K, Nakayama H, Nagata M, Yoshida R, Hirosue A, Tanaka T, Nakagawa Y, Matsuoka Y, Kojima T, Takamune Y, Yoshitake Y, Hiraki A, Shinohara M.
  • Journal Title: Journal of Oral Pathology and Medicine Volume: 35 Pages: 350-6
  • Peer Reviewed
• [Journal Article] Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells. (2014)
  • Author(s): Nakagawa Y, Nakayama H, Nagata M, Yoshida R, Kawahara K, Hirosue A, Tanaka T, Yuno A, Matsuoka Y, Kojima T, Yoshitake Y, Hiraki A, Shinohara M.
  • Journal Title: International journal of cancer Volume: 44 Pages: 1376-84
  • Peer Reviewed
• [Presentation] 巨細胞肉芽腫との鑑別が困難であった下顎頭 に生じた軟骨芽細胞腫の 1 例 (2016)
  • Author(s): 上村 恭子、永田 将士、児玉 彩、吉田 遼司、 平木 昭光、篠原 正徳、三上 芳喜 、中山 秀樹
  • Organizer: 口腔腫瘍学会
  • Place of Presentation: 横浜市開港記念会館
  • Year and Date: 2016-01-21
• [Presentation] 癌抑制遺伝子 Smad4 は口腔白板症の癌化に 関与する (2016)
  • Author(s): 坂田 純基、吉田 遼司、廣末 晃之、松岡 祐一郎、永田 将士、 川原 健太、有田 英生、中嶋 光、上村 恭子、福間 大喜、 尾木 秀直、平木 昭光、篠原 正徳、中山 秀樹
  • Organizer: 口腔腫瘍学会
  • Place of Presentation: 横浜市開港記念会館
  • Year and Date: 2016-01-21
• [Presentation] 口腔癌の化学放射線療法における唾液量の変化に関する臨床的検討 -臨床的影響因子や放射線性粘膜炎との関連について- (2015)
  • Author(s): 有田英生、平木昭光、川原健太、上村恭子、吉田遼司、永田将士、中山秀樹
  • Organizer: 唾液腺学会
  • Place of Presentation: 文教学院大学
  • Year and Date: 2015-12-05
• [Presentation] The clinical significance of FBXW7 in oral squamous cell carcinoma (2015)
  • Author(s): 有田 英生、吉田 遼司、廣末 晃之、松岡 祐一郎、永田 将士、川原 健太、 中川、純泰、坂田 純基、平木 昭光、篠原 正徳、中山 秀樹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] Radioresistance of metastatic tumor cells in oral squamous cell carcinoma (2015)
  • Author(s): 川原健太、吉田遼司、廣末晃之、田中拓也、永田将士、松岡祐一郞、湯野晃、有田英生、 坂田純基、平木昭光、中山秀樹、篠原正徳
  • Organizer: 第39回日本頭頸部癌学会/第4回アジア頭頸部癌学会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-06-04
• [Presentation] In vitro analysis for predictors of cetuximab-sensitivity in human oral cancer cell lines (2014)
  • Author(s): Masashi Nagata, Hideki Nakayama, Yuichiro Matsuoka, Ryoji Yoshida, Hiroko Kihara, Akiyuki Hirosue, Kenta Kawahara, Yoshihiro Nakagawa, Akimitsu Hiraki, Masanori Shinohara
  • Organizer: 第73回 癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 口腔扁平上皮がん細胞株を用いたCetuximab耐性株の樹立と機能解析 (2014)
  • Author(s): 永田将士、中山秀樹、吉田遼司、木原廣子、牧正啓、廣末晃之、田中拓也、川原健太、中川純泰、松岡祐一郎、篠原正徳
  • Organizer: 第38回 頭頸部癌学会
  • Place of Presentation: 東京
  • Year and Date: 2014-06-12 – 2014-06-13