The identification of novel microRNAs regulating cancer stem cell properties and the clinical application to therapeutic strategy in gastrointestinal cancer

• Project/Area Number: 26293290
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: BABA Hideo 熊本大学, 大学院生命科学研究部(医), 教授 (20240905)
• Co-Investigator(Kenkyū-buntansha): 石本 崇胤 熊本大学, 国際先端医学研究機構, 准教授 (00594889) ; 馬場 祥史 熊本大学, 大学院生命科学研究部(医), 講師 (20599708) ; 岩槻 政晃 熊本大学, 大学院生命科学研究部(医), 助教 (50452777) ; 今村 裕 公益財団法人がん研究会, その他部局等, 医員 (70583045) ; 渡邊 雅之 公益財団法人がん研究会, その他部局等, 食道担当部長 (80254639)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 癌幹細胞 / microRNA / 腫瘍微小環境 / 消化器癌 / ニッチ / 循環微量癌細胞 / CD44 / Hippo pathway / Bmi-1 / FBXW7

Outline of Final Research Achievements

Increasing evidence has shown that tumor heterogeneity is a result of the hierarchical organization of cancer stem cells (CSCs), which are strongly associated with tumor relapse and metastasis. Our recent studies have revealed that particular microRNAs are deeply implicated in CSC properties in various types of gastrointestinal cancer. Moreover, we demonstrated that tumor-associated-macrophages and cancer-associated-fibroblasts in tumor microenvironment affect the expression of these microRNAs and promote cancer progression.

Research Products

• [Journal Article] Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. (2017)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang KK, Joyce LN, Kalpana R, Tay ST, Suzuki Y, Cho BC, Kuroda D, Arima K, Izumi D, Iwatsuki M, Baba Y, Oki E, Watanabe M, Saya H, Hirakawa K, Baba H, Tan P.
  • Journal Title: Gastroenterology Volume: in press Issue: 1 Pages: 191-204
  • DOI: 10.1053/j.gastro.2017.03.046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival. (2016)
  • Author(s): Mima K, Nishihara R, Yang J, Dou R, Masugi Y, Shi Y, da Silva A, Cao Y, Song M, Nowak J, Gu M, Li W, Morikawa T, Zhang X, Wu K, Baba H, Giovannucci EL, Meyerhardt JA, Chan AT, Fuchs CS, Qian ZR, Ogino S.
  • Journal Title: Clin Cancer Res Volume: 22(15) Pages: 3841-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MicroRNA MIR21 and T Cells in Colorectal Cancer. (2016)
  • Author(s): Mima K, Nishihara R, Nowak JA, Kim SA, Song M, Inamura K, Sukawa Y, Masuda A, Yang J, Dou R, Nosho K, Baba H, Giovannucci EL, Bowden M, Loda M, Giannakis M, Bass AJ, Dranoff G, Freeman GJ, Chan AT, Fuchs CS, Qian ZR, Ogino S.
  • Journal Title: Cancer Immunol Res Volume: 4(1) Issue: 1 Pages: 33-40
  • DOI: 10.1158/2326-6066.cir-15-0084
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The role of microRNA in esophageal squamous cell carcinoma. (2016)
  • Author(s): Harada K, Baba Y, Ishimoto T, Shigaki H, Kosumi K, Yoshida N, Watanabe M, Baba H.
  • Journal Title: J Gastroenterol Volume: 51(6) Issue: 6 Pages: 520-30
  • DOI: 10.1007/s00535-016-1161-9
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. (2016)
  • Author(s): Tokunaga R, Imamura Y, Nakamura K, Ishimoto T, Nakagawa S, Miyake K, Nakaji Y, Tsuda Y, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Saeki H, Yoshida N, Oki E, Watanabe M, Oda Y, Bass AJ, Maehara Y, Baba H.
  • Journal Title: Oncotarget Volume: in press Issue: 15 Pages: 19748-61
  • DOI: 10.18632/oncotarget.7782
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell-like Behaviors Contributing to Disease Progression. (2015)
  • Author(s): Hayashi H, Higashi T, Yokoyama N, Kaida T, Sakamoto K, Fukushima Y, Ishimoto T, Kuroki H, Nitta H, Hashimoto D, Chikamoto A, Oki E, Beppu T, Baba H.
  • Journal Title: Cancer Res. Volume: 75(22) Issue: 22 Pages: 4985-97
  • DOI: 10.1158/0008-5472.can-15-0291
  • Peer Reviewed / Open Access
• [Journal Article] miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells. (2015)
  • Author(s): Higashi, T., Hayashi, H., Ishimoto, T., Takeyama, H., Kaida, T., Arima, K., Taki, K., Sakamoto, K., Kuroki, H., Okabe, H., Nitta, H., Hashimoto, D., Chikamoto, A., Beppu, T., Baba, H.
  • Journal Title: Br J Cancer Volume: 14;113(2) Issue: 2 Pages: 252-8
  • DOI: 10.1038/bjc.2015.170
  • Peer Reviewed
• [Journal Article] Suppressor microRNA-145 is epigenetically regulated by promoter hypermethylation in esophageal squamous cell carcinoma. (2015)
  • Author(s): Harada K, Baba Y, Ishimoto T, Kosumi K, Tokunaga R, Izumi D, Ohuchi M, Nakamura K, Kiyozumi Y, Kurashige J, Iwagami S, Miyamoto Y, Sakamoto Y, Yoshida N, Oki E, Watanabe M, Baba H
  • Journal Title: Anticancer Res Volume: 35(9) Pages: 4617-24
  • Peer Reviewed
• [Journal Article] Association of microRNA-31-5p with clinical efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer (2015)
  • Author(s): Igarashi H, Kurihara H, Mitsuhashi K, Ito M, Okuda H, Kanno S, Naito T, Yoshii S, Takahashi H, Kusumi T, Hasegawa T, Sukawa Y, Adachi Y, Okita K, Hirata K, Imamura Y, Baba Y, Imai K, Suzuki H, Yamamoto H, Nosho K, Shinomura Y
  • Journal Title: Ann Surg Oncol Volume: 14 Issue: 8 Pages: 4264-4267
  • DOI: 10.1245/s10434-014-4264-7
  • Peer Reviewed / Open Access
• [Journal Article] Noncoding RNA expression aberration is associated with cancer progression and is a potential biomarker in esophageal squamous cell carcinoma (2015)
  • Author(s): Sugihara H., Ishimoto T., Miyake K., Izumi D., Baba Y., Yoshida N., Watanabe M., Baba H
  • Journal Title: Int J Mol Sci Volume: 16 Issue: 11 Pages: 27824-27834
  • DOI: 10.3390/ijms161126060
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of circulating tumor cells derived from advanced gastric cancer. (2015)
  • Author(s): Toyoshima K, Hayashi A, Kashiwagi M, Hayashi N, Iwatsuki M, Ishimoto T, Baba Y, Baba H, Ohta Y
  • Journal Title: Int J Cancer Volume: 137(4) Issue: 4 Pages: 991-8
  • DOI: 10.1002/ijc.29455
  • Peer Reviewed / Open Access
• [Journal Article] The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway (2015)
  • Author(s): Eto K, Iwatsuki M, Watanabe M, Ishimoto T, Ida S, Imamura Y, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Baba H
  • Journal Title: Int J Cancer Volume: 136(7) Issue: 7 Pages: 1537-45
  • DOI: 10.1002/ijc.29168
  • Peer Reviewed
• [Journal Article] Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in cancer cells and promote redox adaptation (2014)
  • Author(s): Ishimoto T, Sugihara H, Watanabe M, Sawayama H, Iwatsuki M, Baba Y, Okabe H, Hidaka K, Yokoyama N, Miyake K, Yoshikawa M, Nagano O, Komohara Y, Takeya M, Saya H, Baba H.
  • Journal Title: Carcinogenesis Volume: 35(5) Issue: 5 Pages: 1003-11
  • DOI: 10.1093/carcin/bgt402
  • Peer Reviewed / Open Access
• [Journal Article] Identification of miR-30e*regulation of Bmi1 expression mediated by tumor-assocated macrophages in gastrointestinal cancer. (2013)
  • Author(s): 117 Sugihara H, Ishimoto T., Watanabe M., Sawayama H., Iwatsuki M., Baba Y., Kamohara Y., Takeya M., Baba H
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: e81839-e81839
  • DOI: 10.1371/journal.pone.0081839
  • Peer Reviewed
• [Presentation] Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas. (2017)
  • Author(s): Arima K、Ishimoto T, Ohmuraya M, Miyake K, Eto T, Okabe H, Kitano Y, Yamamura K, Kaida T, Imai K, Hashimoto D, Chikamoto A, Baba H
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: ワシントン（米国）
  • Int'l Joint Research
• [Presentation] RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk. (2017)
  • Author(s): Ishimoto T, Miyake K, Yashiro M, Eto T, Izumi D, Arima K, Baba Y, Watanabe M, Hirakawa K, Baba H
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: ワシントン（米国）
  • Int'l Joint Research
• [Presentation] 腫瘍間質ゲノム解析に基づいた胃癌浸潤を制御する新規分子機構の解明 (2017)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、江藤二男、有馬浩太、泉大輔、岩槻政晃、馬場祥史、渡邊雅之、平川弘聖、Patrick Tan、馬場秀夫
  • Organizer: 第89回日本胃癌学会総会
  • Place of Presentation: 広島国際会議場（広島県）
• [Presentation] Identification of the novel molecules mediating gastric cancer invasion based on genomic analysis of cancer-associated fibroblasts. (2016)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Huang K, Arima K, Izumi D, Baba Y, Baba H, Tan P
  • Organizer: ESMO-ASIA 2016
  • Place of Presentation: シンガポール
  • Int'l Joint Research
• [Presentation] Verification of mechanism that CSC markers are implicated in poor prognosis for pancreatic ductal adenocarcinoma. (2016)
  • Author(s): Arima K, Ishimoto T, Ohmuraya M, Okabe H, Kitano Y, Yamamura K, Kaida T, Nakagawa S, Imai K, Hashimoto D, Chikamoto A, Yamashita Y, Baba H
  • Organizer: ESMO-ASIA 2016
  • Place of Presentation: シンガポール
  • Int'l Joint Research
• [Presentation] Cancer Associated Fibroblasts (CAFs)ゲノム解析に基づいた胃癌浸潤を制御する新規遺伝子の同定 (2016)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、有馬浩太、泉大輔、澤山浩、岩槻政晃、馬場祥史、坂本快郎、吉田直矢、平川弘聖、馬場秀夫、Patrick Tan
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] がん幹細胞マーカーが膵癌進展を引き起こすメカニズムの解明 (2016)
  • Author(s): 有馬浩太、石本崇胤、大村谷昌樹、三宅慧輔、江藤二男、甲斐田剛圭、東孝暁、岡部弘尚、新田英利、橋本大輔、近本 亮、山下洋市、馬場秀夫
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] 胃癌におけるトラスツズマブ二次耐性に関与するmicroRNAの同定 (2015)
  • Author(s): 岩槻政晃、藏重淳二、江藤弘二郎、糸山明莉、黒田大介、江藤二男、小澄敬祐、馬場祥史、坂本快郎、吉田直矢、馬場秀夫
  • Organizer: 第26回日本消化器癌発生学会
  • Place of Presentation: 米子全日空ホテル（鳥取県）
  • Year and Date: 2015-11-20
• [Presentation] 肝細胞癌進展におけるHippo-pathwayを介した癌幹細胞性獲得機構の解明 (2015)
  • Author(s): 林洋光、東孝暁、坂本慶太、横山奈緒美、武山秀晶、甲斐田剛圭、北野雄希、山村謙介、新田英利、橋本大輔、近本 亮、別府 透、高森啓史、馬場秀夫
  • Organizer: 第26回日本消化器癌発生学会
  • Place of Presentation: 米子全日空ホテル（鳥取県）
  • Year and Date: 2015-11-20
• [Presentation] Suppressor microRNA-145 is epigenetically regulated by promoter hypermethylation in esophageal squamous cell carcinoma (2015)
  • Author(s): Kazuto Harada、Yoshifumi Baba, Keisuke Kosumi, Ryuma Tokunaga, Daisuke Izumi, Mayuko Ouchi, Kennichi Nakamura, Yuki Kiyozumi, Junji Kurashige, Yukiharu Hiyoshi, Shiro Iwagami, Yuji Miyamoato, Yasuo Sakamoto,1 Naoya Yoshida, Masayuki Watanabe, Hideo Baba.
  • Organizer: AACR Annual Meeting 2015
  • Place of Presentation: Pennsylvania Convention Center（米国・フィラデルフィア）
  • Year and Date: 2015-04-21
  • Int'l Joint Research
• [Presentation] Helicobacter pylori Infection causes gastric cancer initiation and progression via miR-328/CD44 signaling. (2015)
  • Author(s): Keisuke Miyake、Takatsugu Ishimoto, Hidetaka Sugihara, Kojiro Eto, Daisuke Izumi, Junji Kurashige, Yukiharu Hiyoshi, Shiro Iwagami, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba.
  • Organizer: AACR Annual Meeting 2015
  • Place of Presentation: Pennsylvania Convention Center（米国・フィラデルフィア）
  • Year and Date: 2015-04-19
  • Int'l Joint Research
• [Presentation] microRNAを標的とした胃癌腹膜播治療標的の探索 (2015)
  • Author(s): 藏重淳二、美馬浩介、岩上志朗、江藤弘二郎、杉原栄孝、泉大輔、小澄敬祐、徳永竜馬、日吉幸晴、宮本裕士、坂本快郎、馬場祥史、吉田直矢、杉町圭史、三森功士、馬場秀夫
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県）
  • Year and Date: 2015-04-17
• [Presentation] Sensitivity to trastuzumab for gastric cancer is regulated by miR-223/FBXW7 pathway (2014)
  • Author(s): Eto K
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, California
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] 胃癌におけるFBXW7 を介したTrastuzumab 耐性機序の解明 (2014)
  • Author(s): 江藤 弘二郎
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-03 – 2014-04-05