Involvement of miRMAs in the interaction between cancer stem cells and tumor micro-environment

• Project/Area Number: 23591920
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: University of Toyama
• Principal Investigator: OKUMURA Tomoyuki 富山大学, 大学院医学薬学研究部(医学), 助教 (10533523)
• Co-Investigator(Kenkyū-buntansha): TSUKADA Kazuhiro 富山大学, 大学院医学薬学研究部(医学), 教授 (90171967) ; SHIMADA Yutaka 京都大学, 薬学研究科(研究院), 寄附講座教員 (30216072)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 食道癌 / miRNA / 癌幹細胞 / マイクロRNA / mir203 / 分化誘導

Research Abstract

Our investigation establishing stable clones from ESCC cell lines with induced miR-203 expression resulted in significant growth inhibition in vitro and in vivo. In p75NTR-negative cells, the expression of p63 was down-regulated and involucrin was up-regulated. Small foci were observed in mouse xenograft tumors with stratified squamous differentiation. The expression of basement membrane protein laminine was localized at the center of the foci and p75NTR-positive cells resided at the basal layer. Our cDNA microarray analysis demonstrated up-regulation of genes involved in regulating tissue polarity, such as BMP-4 and ZO-1. These results demonstrated that miR-203 regulated both self renew of CSLCs and differentiation of non-CSLCs, leading significant tumor growth inhibition with restored epithelial tissue architecture in vivo, which suggests the use of miR-203 as a novel therapeutic target for ESCC.

Research Products

• [Journal Article] Abnormal cell proliferation in the p75NTR-positive basal cell compartment of the esophageal epithelium during squamous carcinogenesis (2014)
  • Author(s): Okumura T, Shimada Y, Sakurai T, Hori R, Nagata T, Sakai Y, Tsukada K
  • Journal Title: Diseases of the Esophagus Volume: 28 Issue: 7 Pages: 634-643
  • DOI: 10.1111/dote.12245
  • Peer Reviewed
• [Journal Article] MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo (2014)
  • Author(s): Okumura T, Shimada Y, Moriyama M, Takei Y, Omura T, Sekine S, Nagata T, Shimizu K, Tsukada K.
  • Journal Title: Int J Oncol Volume: 44(6) Pages: 1923-32
  • Peer Reviewed
• [Journal Article] Expression analysis of fibroblast growth factor receptor-like 1 (FGFRL1) in esophageal squamous cell carcinoma (2014)
  • Author(s): Shimada Y, Okumura T, Nagata T, Hashimoto I, Sawada S, Yoshida Y, Fukuoka J, Shimizu K, Tsukada K
  • Journal Title: Esophagus Volume: 11 Pages: 48-53
  • NAID: 40020229726
  • Peer Reviewed
• [Journal Article] Relapse-associated microRNA in gastric cancer patients after S-1 adjuvant chemotherapy (2014)
  • Author(s): Omura T
  • Journal Title: Oncology Reports Volume: 31 Issue: 2 Pages: 613-618
  • DOI: 10.3892/or.2013.2900
  • Peer Reviewed
• [Journal Article] Clinicopathological significance of deoxycytidine kinase expression in esophageal squamous cell carcinoma (2014)
  • Author(s): Shimada Y, Okumura T, Sekine S, Moriyama M, Hojo S, Matsui K, Sawada S, Nagata T, Fukuoka J, Tsukada K.
  • Journal Title: Mol Clin Oncol Volume: 1(4) Pages: 716-720
  • Peer Reviewed
• [Journal Article] MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo. (2014)
  • Author(s): Okumura T, Shimada Y, Moriyama M, Takei Y, Omura T, Sekine S, Nagata T, Shimizu K, Tsukada K.
  • Journal Title: Int J Oncol Volume: 44 Issue: 6 Pages: 1923-1932
  • DOI: 10.3892/ijo.2014.2365
  • Peer Reviewed
• [Journal Article] Establishment and characterization of a novel xenograft model of human gastrointestinal stromal tumor in mice. (2013)
  • Author(s): Shimada Y, Okumura T, Sekine S, Moriyama M, Sawada S, Matsui K, Yoshioka I, Hojo S, Yoshida T, Nagata T, Fukuoka J, Tsukada K.
  • Journal Title: Anticancer Res Volume: 33 Pages: 175-181
  • Peer Reviewed
• [Journal Article] Expression analysis of iPS cell - inductive genes in esophageal squamous cell carcinoma by tissue microarray (2012)
  • Author(s): Shimada Y, Okumura T, Sekine S, Moriyama M, Sawada S, Matsui K, Yoshioka I, Hojo S, Yoshida T, Nagata T, Fukuoka J, Tsukada K.
  • Journal Title: Anticancer Res. Volume: 32(12) Pages: 5507-14
  • Peer Reviewed
• [Journal Article] Expression analysis of iPS cell - inductive genes in esophageal squamous cell carcinoma by tissue microarray. (2012)
  • Author(s): Shimada Y, Okumura T, Sekine S, Moriyama M, Sawada S, Matsui K, Yoshioka I, Hojo S, Yoshida T, Nagata T, Fukuoka J, Tsukada K.
  • Journal Title: Anticancer Res Volume: 32 Pages: 5507-5514
  • Peer Reviewed
• [Presentation] マイクロRNA203導入による食道扁平上皮癌幹細胞形質の変化 (2014)
  • Author(s): 奥村知之、嶋田裕、渡辺徹、平野勝久、山口哲司、森山亮仁、橋本伊佐也、渋谷和人、神山公希、北條荘三、松井恒志、吉岡伊作、澤田成朗、吉田徹、長田拓哉、武井義則、清水一治、塚田一博
  • 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
• [Presentation] 食道扁平上皮癌における分化制御microRNAの発現と役割 (2013)
  • Author(s): 奥村知之、嶋田裕、森山亮仁、大村哲也、関根慎一、橋本伊佐也、渋谷和人、北條荘三、松井恒志、吉岡伊作、澤田成朗、吉田徹、長田拓哉、塚田一博
  • Organizer: 第11回日本消化器外科学会大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-11
• [Presentation] 食道扁平上皮癌においてmiR-203の発現により増殖が抑制され分化が誘導される (2013)
  • Author(s): T. Okumura, Y. Shimada, M. Moriyama, Y. Takei, T. Yamaguchi, T. Omura, S. Sekine, S. Sawada, T. Nagata, K. Shimizu, K. Tsukada
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-05
• [Presentation] 食道原発小細胞癌と肺原発小細胞癌における遺伝子発現プロファイルの比較 (2013)
  • Author(s): 奥村知之、嶋田裕、山口哲司、森山亮仁、大澤宗士、神山公希、橋本伊佐也、渋谷和人、北條荘三、松井恒志、吉岡伊作、澤田成朗、吉田徹、長田拓哉、塚田一博
  • Organizer: 第24回日本消化器癌発生学会
  • Place of Presentation: 金沢
  • Year and Date: 2013-09-06
• [Presentation] 食道扁平上皮癌における幹細胞制御microRNAの探索とその臨床的意義 (2013)
  • Author(s): 奥村知之、嶋田裕、森山亮仁、大村哲也、関根慎一、渡邊智子、北條荘三、渋谷和人、松井恒志、吉岡伊作、澤田成朗、吉田徹、長田拓哉、塚田一博
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2013-04-12
• [Presentation] 食道扁平上皮癌においてmiR-203 の発現により増殖が抑制され分化が誘導される (2013)
  • Author(s): T. Okumura, Y. Shimada, M. Moriyama, Y. Takei, T. Yamaguchi, T. Omura, S. Sekine, S. Sawada, T. Nagata, K. Shimizu, K. Tsukada
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] microRNAを用いた食道扁平上皮癌分化誘導療法の可能性 (2013)
  • Author(s): 奥村知之、嶋田 裕、森山 亮仁、大村 哲也、関根 慎一、橋本 伊佐也、渋谷 和人、北條 荘三、松井 恒志、吉岡 伊作、澤田 成朗、吉田 徹、長田 拓哉、塚田 一博
  • Organizer: 第1５回 外科分子細胞治療研究会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Identification of microRNAs which regulate stem cell property in esophageal squamous cell carcinoma (2012)
  • Author(s): T. Okumura, Y. Shimada, S. Sekine, M. Moriyama, T. Omura, K. Kamiyama, R. Hori, T. Watanabe, S. Hojo, K. Matsui, I. Yoshioka, S. Sawada, T. Yoshida, T. Nagata, K. Tsukada
  • Organizer: The 13th World Congress of the International Society for Diseases of the Esophagus
  • Place of Presentation: Venice, Italy
  • Year and Date: 2012-10-17
• [Presentation] Identification of microRNAs which regulate stem cell property in esophageal squamous cell carcinoma (2012)
  • Author(s): T. Okumura, Y. Shimada, T. Moriyama. S. Sekine, M. Omura, K. Kamiyama, R. Hori, T. Watanabe, S. Hojo, K. Matsui, I. Yoshioka, S. Sawada, T. Yoshida, T. Nagata, K. Tsukada
  • Organizer: 第67回日本消化器外科学会総会
  • Place of Presentation: 富山
• [Presentation] Identification of micrornas whichregulate stem cell property in esophageal squamous cell carcinoma (2012)
  • Author(s): Okumura T、Shimada Y, Sekine S, Moriyama M, Omura T, Kamiyama K, Hori R, Watanabe T, Hojo S, Matsui K, Yoshioka I, Sawada S, Yoshida T, Nagata T, Tsukada K
  • Organizer: 13rd World Congress of the international society for diseases of the esophagus
  • Place of Presentation: ベニス、イタリア
• [Presentation] 食道扁平上皮癌における腫瘍幹細胞の同定とその制御分子の探索 (2012)
  • Author(s): 奥村知之、嶋田 裕，関根慎一，森山亮仁，大村哲也，神山公希，北條荘三，堀 亮太，長田拓哉，塚田一博
  • Organizer: 第６６回日本食道学会学術集会
  • Place of Presentation: 軽井沢
• [Presentation] Identification of microRNAs which are differentially expressed in p75NTR-positive esophageal squamous cell carcinoma (2011)
  • Author(s): Okumura T., Shimada Y., Osawa S., Sekine S., Moriyama M., Omura T., and Tsukada K.
  • Organizer: International Surgical Week /ISW2011
  • Place of Presentation: Yokohama
• [Presentation] Identification of microRNAs which are differentially expressed in p75NTR-positive esophageal squamous cell carcinoma (2011)
  • Author(s): Tomoyuki Okumura, Yutaka Shimada, Soshi Osawa, Shinichi Sekine, Makoto Moriyama, Tetsuya Omura, Kazuhiro Tsukada
  • Organizer: International Surgical Week ISW 2011
  • Place of Presentation: Yokohama, Japan
• [Presentation] 食道癌幹細胞を標的とした食道癌治療の可能性 (2011)
  • Author(s): 奥村知之、嶋田 裕 、関根慎一、森山亮仁、大村哲也、河合俊輔、橋本伊佐也、北條荘三、渡邊智子、堀 亮太、松井恒志、吉岡伊作 、澤田成明、吉田 徹、長田拓哉、魚谷英之、塚田一博
  • Organizer: 第29回日本ヒト細胞学会学術集会
  • Place of Presentation: 富山