Analysis of driver gene mutation using organoid model

• Project/Area Number: 18K07016
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Hiroshima University
• Principal Investigator: Oue Naohide 広島大学, 医系科学研究科(医), 准教授 (60346484)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 胃癌 / 幹細胞 / 大腸癌 / 癌幹細胞 / 薬剤耐性 / スフェロイド / QPRT / オルガノイド

Outline of Final Research Achievements

Spheroid colony formation is a useful method of cancer stem cell characterization. We found that QPRT、CST2、ANKRD45、ZWINT、FAM111B gene is up-regulated in spheroid body-forming cancer cells compared with parental cells. We investigated ZWINT expression in colorectal cancer. Immunohistochemical analysis demonstrated that 61 (47%) of 129 colorectal cancer cases were positive for ZWINT and ZWINT expression was significantly correlated with KIFC1 expression. ZWINT-positive cases exhibited significantly worse overall survival. KIFC1 siRNA-transfected cells showed reduced ZWINT expression while ZWINT siRNA-transfected cells decreased cell proliferation. Both KIFC1 and ZWINT knockdown cells attenuated spheroid formation ability. This study provides new insights into KIFC1 regulating ZWINT in colorectal cancer progression and its potential as a therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

ZWINTは47%の大腸癌で高発現しおり、高発現例は有意に予後不良であったことから、大腸癌の予後予測マーカーとして有用である。さらにZWINTは癌幹細胞のマーカーであるKIFC1陽性細胞において発現していたことから、幹細胞において重要な役割を果たしている可能性もあり、治療標的としても期待される。

Research Products

• [Journal Article] Clinicopathological significance of intelectin‐1 in colorectal cancer: Intelectin‐1 participates in tumor suppression and favorable progress (2020)
  • Author(s): Katsuya Narutaka、Sentani Kazuhiro、Sekino Yohei、Yamamoto Yuji、Kobayashi Go、Babasaki Takashi、Oue Naohide、Amatya Vishwa Jeet、Takeshima Yukio、Yasui Wataru
  • Journal Title: Pathology International Volume: 70 Issue: 12 Pages: 943-952
  • DOI: 10.1111/pin.13027
  • Peer Reviewed / Open Access
• [Journal Article] linical significance of glioma-associated oncogene 1 expression in patients with locally advanced gastric cancer administered adjuvant chemotherapy with S-1 after curative surgery (2020)
  • Author(s): Hashimoto I, Oue N, Kimura Y, Hiroshima Y, Hara K, Maezawa Y, Kano K, Fujikawa H, Aoyama T, Numata M, Yamada T, Tamagawa H, Yamamoto N, Ogata T, Shiozawa M, Morinaga S, Rino Y, Yasui W, Masuda M, Miyagi Y, Oshima T
  • Journal Title: Anticancer Res Volume: 40 Issue: 10 Pages: 5815-5821
  • DOI: 10.21873/anticanres.14599
  • Peer Reviewed
• [Journal Article] Oncogenic mutation in RAS‐RAF axis leads to increased expression of GREB1, resulting in tumor proliferation in colorectal cancer (2020)
  • Author(s): Kochi Masatoshi、Hinoi Takao、Niitsu Hiroaki、Miguchi Masashi、Saito Yasufumi、Sada Haruki、Sentani Kazuhiro、Sakamoto Naoya、Oue Naohide、Tashiro Hirotaka、Sotomaru Yusuke、Yasui Wataru、Ohdan Hideki
  • Journal Title: Cancer Science Volume: 111 Issue: 10 Pages: 3540-3549
  • DOI: 10.1111/cas.14558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microtubule-associated protein tau (MAPT) is a promising independent prognostic marker and tumor suppressive protein in clear cell renal cell carcinoma. (2020)
  • Author(s): Han X, Sekino Y, Babasaki T, Goto K, Inoue S, Hayashi T, Teishima J, Sakamoto N, Sentani K, Oue N, Yasui W, Matsubara A.
  • Journal Title: Urol Oncol. Volume: - Issue: 6 Pages: 9-17
  • DOI: 10.1016/j.urolonc.2020.02.010
  • Peer Reviewed / Open Access
• [Journal Article] Claspin overexpression is associated with high-grade histology and poor prognosis in renal cell carcinoma. (2020)
  • Author(s): Kobayashi G, Sentani K, Babasaki T, Sekino Y, Shigematsu Y, Hayashi T, Oue N, Teishima J, Matsubara A, Sasaki N, Yasui W.
  • Journal Title: Cancer Sci. Volume: 111(3) Issue: 3 Pages: 1020-1027
  • DOI: 10.1111/cas.14299
  • Peer Reviewed / Open Access
• [Journal Article] TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma (2020)
  • Author(s): Sekino Yohei、Han Xiangrui、Babasaki Takashi、Miyamoto Shunsuke、Kitano Hiroyuki、Kobayashi Go、Goto Keisuke、Inoue Shogo、Hayashi Tetsutaro、Teishima Jun、Sakamoto Naoya、Sentani Kazuhiro、Oue Naohide、Yasui Wataru、Matsubara Akio
  • Journal Title: Oncology Volume: 98 Issue: 10 Pages: 689-698
  • DOI: 10.1159/000506775
  • Peer Reviewed / Open Access
• [Journal Article] SPC18 Expression Is an Independent Prognostic Indicator of Patients with Esophageal Squamous Cell Carcinoma (2020)
  • Author(s): Yamamoto Yuji、Oue Naohide、Asai Ryuichi、Katsuya Narutaka、Uraoka Naohiro、Sakamoto Naoya、Sentani Kazuhiro、Tanabe Kazuaki、Ohdan Hideki、Yasui Wataru
  • Journal Title: Pathobiology Volume: 87 Issue: 4 Pages: 254-261
  • DOI: 10.1159/000506956
  • Peer Reviewed / Open Access
• [Journal Article] Role of Metastasis-Related Genes in Cisplatin Chemoresistance in Gastric Cancer (2019)
  • Author(s): Nishiguchi Yukiko、Oue Naohide、Fujiwara-Tani Rina、Sasaki Takamitsu、Ohmori Hitoshi、Kishi Shingo、Mori Shiori、Mori Takuya、Ikeda Naoya、Matsumoto Sohei、Wakatsuki Kohei、Luo Yi、Yasui Wataru、Sho Masayuki、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 1 Pages: 254-254
  • DOI: 10.3390/ijms21010254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Significance of PRKCI Gene Expression in Cancerous Tissue in Patients With Gastric Cancer (2019)
  • Author(s): HASHIMOTO ITARU、SAKAMAKI KENTARO、OUE NAOHIDE、KIMURA YAYOI、HIROSHIMA YUKIHIKO、HARA KENTARO、MAEZAWA YUKIO、KANO KAZUKI、AOYAMA TORU、YAMADA TAKANOBU、YAMAMOTO NAOTO、OGATA TAKASHI、ITO HIROYUKI、SHIOZAWA MANABU、MORINAGA SOICHIRO、RINO YASUSHI、YASUI WATARU、MASUDA MUNETAKA、MIYAGI YOHEI、OSHIMA TAKASHI
  • Journal Title: Anticancer Research Volume: 39 Issue: 10 Pages: 5715-5720
  • DOI: 10.21873/anticanres.13771
  • Peer Reviewed
• [Journal Article] miR-130b Promotes Sunitinib Resistance through Regulation of PTEN in Renal Cell Carcinoma (2019)
  • Author(s): Sekino Yohei、Sakamoto Naoya、Sentani Kazuhiro、Oue Naohide、Teishima Jun、Matsubara Akio、Yasui Wataru
  • Journal Title: Oncology Volume: 97 Issue: 3 Pages: 164-172
  • DOI: 10.1159/000500605
  • Peer Reviewed / Open Access
• [Journal Article] CD204-Positive Tumor-associated Macrophages Relate to Malignant Transformation of Colorectal Adenoma (2019)
  • Author(s): TANIYAMA DAIKI、TANIYAMA KIYOMI、KURAOKA KAZUYA、YAMAMOTO HIDEKI、ZAITSU JUNICHI、SAITO AKIHISA、SAKAMOTO NAOYA、SENTANI KAZUHIRO、OUE NAOHIDE、YASUI WATARU
  • Journal Title: Anticancer Research Volume: 39 Issue: 6 Pages: 2767-2775
  • DOI: 10.21873/anticanres.13403
  • Peer Reviewed
• [Journal Article] Correction: Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-α secretion in gastric cancer (2019)
  • Author(s): Oue N、Naito Y、Hayashi T、Takigahira M、Kawano-Nagatsuma A、Sentani K、Sakamoto N、Oo H Z、Uraoka N、Yanagihara K、Ochiai A、Sasaki H、Yasui W
  • Journal Title: Oncogene Volume: 38 Issue: 28 Pages: 5748-5748
  • DOI: 10.1038/s41388-019-0837-z
  • Peer Reviewed
• [Journal Article] SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival (2019)
  • Author(s): Shigematsu Yoshinori、Oue Naohide、Sekino Yohei、Sakamoto Naoya、Sentani Kazuhiro、Uraoka Naohiro、Hayashi Tetsutaro、Teishima Jun、Matsubara Akio、Yasui Wataru
  • Journal Title: Pathobiology Volume: 86 Issue: 4 Pages: 208-216
  • DOI: 10.1159/000497206
  • Peer Reviewed / Open Access
• [Journal Article] Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. (2019)
  • Author(s): Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W.
  • Journal Title: Int J Clin Oncol Volume: 95 Pages: 668-672
  • Peer Reviewed
• [Journal Article] KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer. (2019)
  • Author(s): Sekino Y, Oue N, Koike Y, Shigematsu Y, Sakamoto N, Sentani K, Teishima J, Shiota M, Matsubara A, Yasui W.
  • Journal Title: J Clin Med. Volume: 8 Issue: 2 Pages: 225-225
  • DOI: 10.3390/jcm8020225
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological significance of RCAN2 production in gastric carcinoma. (2019)
  • Author(s): Hattori Y, Sentani K, Shinmei S, Oo HZ, Hattori T, Imai T, Sekino Y, Sakamoto N, Oue N, Niitsu H, Hinoi T, Ohdan H, Yasui W.
  • Journal Title: Histopathology Volume: 74 Issue: 3 Pages: 430-442
  • DOI: 10.1111/his.13764
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer. (2019)
  • Author(s): Kobayashi G, Sentani K, Hattori T, Yamamoto Y, Imai T, Sakamoto N, Kuraoka K, Oue N, Sasaki N, Taniyama K, Yasui W.
  • Journal Title: Hum Pathol Volume: 84 Pages: 8-17
  • DOI: 10.1016/j.humpath.2018.09.001
  • Peer Reviewed
• [Journal Article] Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice (2018)
  • Author(s): Abe Tomoyuki、Tanaka Yuka、Piao Jinlian、Tanimine Naoki、Oue Naohide、Hinoi Takao、Garcia Noel Verjan、Miyasaka Masayuki、Matozaki Takashi、Yasui Wataru、Ohdan Hideki
  • Journal Title: Annals of Gastroenterological Surgery Volume: 2 Issue: 6 Pages: 451-462
  • DOI: 10.1002/ags3.12205
  • Peer Reviewed / Open Access
• [Journal Article] Uc.416+A promotes epithelial-to-mesenchymal transition through miR-153 in renal cell carcinoma (2018)
  • Author(s): Sekino Yohei、Sakamoto Naoya、Goto Keisuke、Honma Ririno、Shigematsu Yoshinori、Quoc Thang Pham、Sentani Kazuhiro、Oue Naohide、Teishima Jun、Kawakami Fumi、Karam Jose A、Sircar Kanishka、Matsubara Akio、Yasui Wataru
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 952-952
  • DOI: 10.1186/s12885-018-4863-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma (2018)
  • Author(s): Pham Quoc Thang、Oue Naohide、Sekino Yohei、Yamamoto Yuji、Shigematsu Yoshinori、Sakamoto Naoya、Sentani Kazuhiro、Uraoka Naohiro、Yasui Wataru
  • Journal Title: Oncology Volume: 95 Issue: 5 Pages: 297-308
  • DOI: 10.1159/000490725
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Silencing of Discoidin Domain Receptor-1 (DDR1) Concurrently Inhibits Multiple Steps of Metastasis Cascade in Gastric Cancer (2017)
  • Author(s): Yuge R, Kitadai Y, Takigawa H, Naito T, Oue N, Yasui W, Tanaka S, Chayama K
  • Journal Title: Transl Oncol Volume: 11 Issue: 3 Pages: 575-584
  • DOI: 10.1016/j.tranon.2018.02.003
  • Peer Reviewed / Open Access
• [Presentation] MCOLN3は胃癌の5-FU抵抗性に関与する (2020)
  • Author(s): 大上直秀、浅井竜一、山本悠司、赤羽慎太郎、坂本直也、仙谷和弘、安井 弥
  • Organizer: 第92回日本胃癌学会総会
• [Presentation] 羅的遺伝子発現解析による胃がんの発生・進展の理解 (2020)
  • Author(s): 大上直秀、山本悠司、浅井竜一、國安弘基、仙谷和弘、坂本直也、大段秀樹、吉田和弘、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] MCOLN3 is involved in 5-FU-resistance in human gastric cancer (2020)
  • Author(s): 大上直秀、浅井竜一、山本悠司、赤羽慎太郎、坂本直也、仙谷和弘、安井 弥
  • Organizer: 第109回日本病理学会総会
• [Presentation] 胃癌におけるMCOLN3の高発現は5-FU耐性に関与している (2020)
  • Author(s): 大上直秀、浅井竜一、山本悠司、赤羽慎太郎、仙谷和弘、安井 弥
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 胃癌の進展におけるDSG1遺伝子の発現と意義 (2019)
  • Author(s): 大上直秀、山本悠司、浅井竜一、赤羽慎太郎、坂本直也、仙谷和弘、安井 弥
  • Organizer: 第28回日本がん転移学会学術集会・総会
  • Invited
• [Presentation] 食道扁平上皮癌におけるprotocadherin B9の発現機能解析 (2019)
  • Author(s): 大上直秀、山本悠司、浅井竜一、藤木佑斗、坂本直也、仙谷和弘、安井 弥
  • Organizer: 第108回日本病理学会総会
• [Presentation] 食道扁平上皮癌におけるProtocadherin B9の発現と腫瘍の進行との関連 (2019)
  • Author(s): 大上直秀、藤木佑斗、浅井竜一、浦岡直礼、坂本直也、仙谷和弘、安井 弥
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Precision medicineを目指したオルガノイドモデルによる胃がんの薬剤効果判定 (2018)
  • Author(s): 大上直秀、坂本直也、本間りりの、仙谷和弘、安井 弥
  • Organizer: 第107回日本病理学会総会
  • Invited
• [Presentation] トランスクリプトームによる胃がんの発生・進展の理解 (2018)
  • Author(s): 大上直秀、山本悠司、今井健晴、國安弘基、仙谷和弘、坂本直也、大段秀樹、吉田和弘、安井 弥
  • Organizer: 第29回日本消化器癌発生学会総会
  • Invited
• [Remarks] 広島大学大学院 医系科学研究科 分子病理学
  • URL: https://byori1.hiroshima-u.ac.jp/index.html
• [Remarks] 広島大学大学院医系科学研究科分子病理学
  • URL: https://home.hiroshima-u.ac.jp/byori1/index.html