胃癌発生の初期段階に検出される正常胃粘膜の遺伝子・遺伝子発現異常

• Project/Area Number: 21K06904
• 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: 大上 直秀 広島大学, 医系科学研究科(医), 教授 (60346484)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Discontinued (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 胃癌 / 癌幹細胞 / PD-L1 / 大腸癌 / スフェロイド / ALDOC / 診断 / 治療

Outline of Research at the Start

進行胃癌のうち低分化腺癌は未だ予後不良の疾患であり、新規診断マーカー・治療標的の同定が急務となっている。胃の低分化腺癌のドライバー変異としてRHOA、CDH1遺伝子の変異が報告されたが、これらが発癌過程にどのように関わっているのか全く分かっていない。そこで本研究では、RHOA、CDH1の変異により特異的に発現が誘導される遺伝子を同定し、胃癌の病態解明を通して新規診断マーカー・治療開発に資することである。

Outline of Annual Research Achievements

進行胃癌のうち低分化腺癌は未だに予後不良の疾患であり、新規診断マーカー・治療標的の同定が急務となっている。本研究の目的は、RHOA、CDH1の変異により特異的に発現が誘導される遺伝子を同定し、胃癌の病態解明を通して新規診断マーカー・治療開発に資することである。TDO2が胃癌の進行に重要な役割を担っていることが知られている。本研究では、胃癌におけるTDO2の発現と、炎症細胞浸潤、PD-L1の発現について検討を行った。
TDO2は胃癌において高発現しており、公共データベースによる検討では、TDO2高発現例は有意に予後不良であった。また、TDO2の発現はリンパ球浸潤、PD-1L1の発現と相関する傾向にあった。
胃癌細胞株を材料にTDO2の発現をRNAiでノックダウンし、各種機能解析を行った。TDO2をノックダウンすると、細胞増殖能、コロニー形成能、浸潤能が抑制された。さらにTDO2のノックダウンにより、スフェロイドの形成能が低下し、オルガノイドの形成能も阻害された。
以上の結果から、胃癌においてTDO2は癌細胞の進展に寄与し、予後不良に関わっていることが示唆された。TDO2陽性例はPD-1L1も陽性であることから、TDO2陽性例に対しては抗PD-L2抗体が有効な治療薬となる可能性が高い。TDO2は食道扁平上皮癌、膀胱尿路上皮癌、腎臓腎細胞癌においても高発現しており、癌幹細胞との関連が報告されている。胃癌においてもTDO2阻害によりスフェロイド形成やオルガノイド形成が阻害されたことから、TDO2は胃癌幹細胞の維持に重要な役割を担っていると考えられ、癌幹細胞に対する治療標的としても有用である。

Research Products

• [Journal Article] Expression of kinesin family member C1 in pancreatic ductal adenocarcinoma affects tumor progression and stemness (2023)
  • Author(s): Ishikawa Akira、Fujii Hiroki、Fukui Takafumi、Kido Aya、Katsuya Narutaka、Sentani Kazuhiro、Kuraoka Kazuya、Tazuma Sho、Sudo Takeshi、Serikawa Masahiro、Oka Shiro、Oue Naohide
  • Journal Title: Pathology - Research and Practice Volume: 241 Pages: 154277-154277
  • DOI: 10.1016/j.prp.2022.154277
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of<i>SEC11A</i>Expression in Patients With Locally Advanced Gastric Cancer (2022)
  • Author(s): SUEMATSU HIDEAKI、SAKAMAKI KENTARO、OUE NAOHIDE、HIROSHIMA YUKIHIKO、KIMURA YAYOI、ONUMA SHIZUNE、HASHIMOTO ITARU、NAGASAWA SHINSUKE、AOYAMA TORU、YAMADA TAKANOBU、TAMAGAWA HIROSHI、OGATA TAKASHI、RINO YASUSHI、MASUDA MUNETAKA、YASUI WATARU、MIYAGI YOHEI、OSHIMA TAKASHI
  • Journal Title: Anticancer Research Volume: 42 Issue: 12 Pages: 5885-5890
  • DOI: 10.21873/anticanres.16097
  • Peer Reviewed
• [Journal Article] Histological variants and lymphovascular invasion in upper tract urothelial carcinoma can stratify prognosis after radical nephroureterectomy (2022)
  • Author(s): Takemoto Kenshiro、Hayashi Tetsutaro、Hsi Ryan S.、Kobatake Kohei、Sekino Yohei、Kitano Hiroyuki、Ikeda Kenichiro、Goto Keisuke、Hieda Keisuke、Sentani Kazuhiro、Kajiwara Mitsuru、Nishizaka Takashi、Teishima Jun、Oue Naohide、Hinata Nobuyuki
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 40 Issue: 12 Pages: 539.e9-539.e16
  • DOI: 10.1016/j.urolonc.2022.08.010
  • Peer Reviewed
• [Journal Article] Two case reports of immune checkpoint therapy on chromophobe renal cell carcinoma with sarcomatoid differentiation (2022)
  • Author(s): Fukushima Takafumi、Teishima Jun、Goto Keisuke、Takemoto Kenshiro、Sekino Yohei、Kobatake Kohei、Ikeda Kenichiro、Hayashi Tetsutaro、Sentani Kazuhiro、Oue Naohide、Hinoi Takao、Hinata Nobuyuki
  • Journal Title: International Cancer Conference Journal Volume: 11 Issue: 4 Pages: 286-291
  • DOI: 10.1007/s13691-022-00561-y
  • Peer Reviewed
• [Journal Article] Clinicopathological significance of the overexpression of MUC1 in upper tract urothelial carcinoma and possible application as a diagnostic marker (2022)
  • Author(s): Kobayashi Go、Hayashi Tetsutaro、Sentani Kazuhiro、Takemoto Kenshiro、Sekino Yohei、Uraoka Naohiro、Hanamoto Masanori、Nose Hiroyuki、Teishima Jun、Arihiro Koji、Hinata Nobuyuki、Oue Naohide
  • Journal Title: Pathology International Volume: 72 Issue: 12 Pages: 606-616
  • DOI: 10.1111/pin.13274
  • Peer Reviewed
• [Journal Article] Identification of a Biomarker Combination for Survival Stratification in pStage II/III Gastric Cancer after Curative Resection (2022)
  • Author(s): Hashimoto Itaru、Kimura Yayoi、Oue Naohide、Hiroshima Yukihiko、Aoyama Toru、Rino Yasushi、Yokose Tomoyuki、Yasui Wataru、Miyagi Yohei、Oshima Takashi
  • Journal Title: Cancers Volume: 14 Issue: 18 Pages: 4427-4427
  • DOI: 10.3390/cancers14184427
  • Peer Reviewed
• [Journal Article] Four cases of cytokine storm after COVID-19 vaccination: Case report (2022)
  • Author(s): Murata Kazuhiro、Nakao Naoki、Ishiuchi Naoki、Fukui Takafumi、Katsuya Narutaka、Fukumoto Wataru、Oka Hiroko、Yoshikawa Naotaka、Nagao Takafumi、Namera Akira、Kakimoto Naoya、Oue Naohide、Awai Kazuo、Yoshimoto Kanji、Nagao Masataka
  • Journal Title: Frontiers in Immunology Volume: 13
  • DOI: 10.3389/fimmu.2022.967226
  • Peer Reviewed
• [Journal Article] Histopathology and Cytology of Pulmonary Myoepithelial Neoplasms: 2 Cases (2022)
  • Author(s): Ishikawa Akira、Fujisawa Hiroki、Yasumura Naoko、Kuraoka Kazuya、Zaitsu Junichi、Saito Akihisa、Kan Arisa、Iwahiro Kazue、Kimura Fumika、Tadokoro Kazuki、Tsubokawa Norifumi、Mimura Takeshi、Yamashita Yoshinori、Taniyama Kiyomi、Oue Naohide
  • Journal Title: Case Reports in Oncology Volume: 15 Issue: 2 Pages: 599-605
  • DOI: 10.1159/000524769
  • Peer Reviewed
• [Journal Article] Minichromosome Maintenance 4 Is Associated with Cancer Stemness and Poor Survival of Patients with Gastric Cancer (2022)
  • Author(s): Katsuya Narutaka、Ishikawa Akira、Kido Aya、Fukui Takafumi、Kobayashi Go、Sekino Yohei、Uraoka Naohiro、Babasaki Takashi、Yasui Wataru、Sentani Kazuhiro、Oue Naohide
  • Journal Title: Pathobiology Volume: - Issue: 3 Pages: 1-8
  • DOI: 10.1159/000525590
  • Peer Reviewed
• [Journal Article] ANXA10 Expression Is Inversely Associated with Tumor Stage, Grade, and TP53 Expression in Upper and Lower Urothelial Carcinoma (2022)
  • Author(s): Kobayashi Go、Hayashi Tetsutaro、Sentani Kazuhiro、Ikeda Kenichiro、Babasaki Takashi、Shigematsu Yoshinori、Sekino Yohei、Uraoka Naohiro、Teishima Jun、Matsubara Akio、Hinata Nobuyuki、Oue Naohide
  • Journal Title: Pathobiology Volume: - Issue: 2 Pages: 1-10
  • DOI: 10.1159/000524989
  • Peer Reviewed
• [Journal Article] Essential Roles of TDO2 in Gastric Cancer: TDO2 Is Associated with Cancer Progression, Patient Survival, PD-L1 Expression, and Cancer Stem Cells (2022)
  • Author(s): Pham Quoc Thang、Taniyama Daiki、Akabane Shintaro、Takashima Tsuyoshi、Maruyama Ryota、Sekino Yohei、Sentani Kazuhiro、Yasui Wataru、Oue Naohide
  • Journal Title: Pathobiology Volume: 90 Issue: 1 Pages: 44-55
  • DOI: 10.1159/000523750
  • Peer Reviewed
• [Journal Article] Cytological findings of metastatic poorly differentiated prostate adenocarcinoma to Virchow's node with immunohistochemical positivity for CD10 and negativity for PSA (2022)
  • Author(s): Kobayashi Go、Sentani Kazuhiro、Uraoka Naohiro、Oue Naohide、Sasaki Naomi
  • Journal Title: Cytopathology Volume: 33 Issue: 6 Pages: 749-753
  • DOI: 10.1111/cyt.13149
  • Peer Reviewed
• [Journal Article] Protocadherin B9 Is Associated with Tumorigenesis and Cancer Progression in Colorectal Cancer (2022)
  • Author(s): Asai Ryuichi、Taniyama Daiki、Oue Naohide、Yamamoto Yuji、Akabane Shintaro、Sentani Kazuhiro、Ohdan Hideki、Yoshida Kazuhiro、Yasui Wataru
  • Journal Title: Pathobiology Volume: 89 Issue: 4 Pages: 214-221
  • DOI: 10.1159/000521566
  • Peer Reviewed
• [Journal Article] Protocadherin B9 Is Associated with Human Esophageal Squamous Cell Carcinoma Progression (2022)
  • Author(s): Fujiki Yuto、Ishikawa Akira、Akabane Shintaro、Mukai Shoichiro、Maruyama Ryota、Yamamoto Yuji、Kido Aya、Katsuya Narutaka、Taniyama Daiki、Sentani Kazuhiro、Oue Naohide、Yasui Wataru
  • Journal Title: Pathobiology Volume: - Issue: 1 Pages: 1-9
  • DOI: 10.1159/000523817
  • Peer Reviewed
• [Journal Article] Investigation of endoscopic findings in nine cases of Helicobacter suis‐infected gastritis complicated by gastric mucosa‐associated lymphoid tissue lymphoma (2022)
  • Author(s): Kadota Hiroki、Yuge Ryo、Miyamoto Ryo、Otani Rina、Takigawa Hidehiko、Hayashi Ryohei、Urabe Yuji、Oka Shiro、Sentani Kazuhiro、Oue Naohide、Kitadai Yasuhiko、Tanaka Shinji
  • Journal Title: Helicobacter Volume: - Issue: 3 Pages: 12887-12887
  • DOI: 10.1111/hel.12887
  • Peer Reviewed
• [Journal Article] Overexpression of aldolase, fructose‐bisphosphate C and its association with spheroid formation in colorectal cancer (2022)
  • Author(s): Maruyama Ryota、Nagaoka Yuma、Ishikawa Akira、Akabane Shintaro、Fujiki Yuto、Taniyama Daiki、Sentani Kazuhiro、Oue Naohide
  • Journal Title: Pathology International Volume: 72 Issue: 3 Pages: 176-186
  • DOI: 10.1111/pin.13200
  • Peer Reviewed
• [Journal Article] Cytological and histological findings of upper tract mucinous urothelial carcinoma with clear cell component: A case report and review of literature (2021)
  • Author(s): Kobayashi Go、Uraoka Naohiro、Sentani Kazuhiro、Shibata Jun、Nobuhiro Ryosuke、Saito Yoichi、Taniyama Daiki、Hanamoto Masanori、Nose Hiroyuki、Oue Naohide
  • Journal Title: Diagnostic Cytopathology Volume: 50 Issue: 5
  • DOI: 10.1002/dc.24921
  • Peer Reviewed
• [Journal Article] Clinicopathological significance of claspin overexpression and its efficacy as a novel biomarker for the diagnosis of urothelial carcinoma (2021)
  • Author(s): Kobayashi Go、Hayashi Tetsutaro、Sentani Kazuhiro、Babasaki Takashi、Sekino Yohei、Inoue Shogo、Uraoka Naohiro、Hanamoto Masanori、Nose Hiroyuki、Teishima Jun、Oue Naohide、Matsubara Akio、Sasaki Naomi、Yasui Wataru
  • Journal Title: Virchows Archiv Volume: 480 Issue: 3 Pages: 621-633
  • DOI: 10.1007/s00428-021-03239-7
  • Peer Reviewed
• [Journal Article] KIFC1 Is Associated with Basal Type, Cisplatin Resistance, PD-L1 Expression and Poor Prognosis in Bladder Cancer (2021)
  • Author(s): Sekino Yohei、Pham Quoc Thang、Kobatake Kohei、Kitano Hiroyuki、Ikeda Kenichiro、Goto Keisuke、Hayashi Tetsutaro、Nakahara Hikaru、Sentani Kazuhiro、Oue Naohide、Yasui Wataru、Teishima Jun、Hinata Nobuyuki
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 21 Pages: 4837-4837
  • DOI: 10.3390/jcm10214837
  • Peer Reviewed / Open Access
• [Journal Article] CD44 Is Involved in Sunitinib Resistance and Poor Progression-free Survival After Sunitinib Treatment of Renal Cell Carcinoma (2021)
  • Author(s): SEKINO YOHEI、TAKEMOTO KENSHIRO、MURATA DAIKI、BABASAKI TAKASHI、KOBATAKE KOHEI、KITANO HIROYUKI、IKEDA KENICHIRO、GOTO KEISUKE、INOUE SHOGO、HAYASHI TETSUTARO、TANIYAMA DAIKI、SHIGETA MASANOBU、KURAOKA KAZUYA、MITA KOJI、KANEKO MAYUMI、SENTANI KAZUHIRO、OUE NAOHIDE、TEISHIMA JUN
  • Journal Title: Anticancer Research Volume: 41 Issue: 10 Pages: 4875-4883
  • DOI: 10.21873/anticanres.15301
  • Peer Reviewed
• [Journal Article] P53 Is Involved in Sunitinib Resistance and Poor Progression-free Survival After Sunitinib Treatment of Renal Cell Carcinoma (2021)
  • Author(s): SEKINO YOHEI、TAKEMOTO KENSHIRO、MURATA DAIKI、BABASAKI TAKASHI、KOBATAKE KOHEI、KITANO HIROYUKI、IKEDA KENICHIRO、GOTO KEISUKE、INOUE SHOGO、HAYASHI TETSUTARO、TANIYAMA DAIKI、SHIGETA MASANOBU、KURAOKA KAZUYA、MITA KOJI、KANEKO MAYUMI、SENTANI KAZUHIRO、OUE NAOHIDE、TEISHIMA JUN
  • Journal Title: Anticancer Research Volume: 41 Issue: 9 Pages: 4287-4294
  • DOI: 10.21873/anticanres.15233
  • Peer Reviewed
• [Journal Article] Overexpression of claspin promotes docetaxel resistance and is associated with prostate‐specific antigen recurrence in prostate cancer (2021)
  • Author(s): Babasaki Takashi、Sentani Kazuhiro、Sekino Yohei、Kobayashi Go、Thang Pham Quoc、Katsuya Narutaka、Akabane Shintaro、Taniyama Daiki、Hayashi Tetsutaro、Shiota Masaki、Oue Naohide、Teishima Jun、Matsubara Akio、Yasui Wataru
  • Journal Title: Cancer Medicine Volume: 10 Issue: 16 Pages: 5574-5588
  • DOI: 10.1002/cam4.4113
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathologic features of TDO2 overexpression in renal cell carcinoma (2021)
  • Author(s): Pham Quoc Thang、Taniyama Daiki、Sekino Yohei、Akabane Shintaro、Babasaki Takashi、Kobayashi Go、Sakamoto Naoya、Sentani Kazuhiro、Oue Naohide、Yasui Wataru
  • Journal Title: BMC Cancer Volume: 21 Issue: 1 Pages: 737-737
  • DOI: 10.1186/s12885-021-08477-1
  • Peer Reviewed / Open Access
• [Journal Article] TDO2 overexpression correlates with poor prognosis, cancer stemness, and resistance to cetuximab in bladder cancer (2021)
  • Author(s): Pham Quoc Thang、Taniyama Daiki、Akabane Shintaro、Harada Kenji、Babasaki Takashi、Sekino Yohei、Hayashi Tetsuraro、Sakamoto Naoya、Sentani Kazuhiro、Oue Naohide、Yasui Wataru
  • Journal Title: Cancer Reports Volume: 4 Issue: 6
  • DOI: 10.1002/cnr2.1417
  • Peer Reviewed / Open Access
• [Journal Article] KIFC1 regulates ZWINT to promote tumor progression and spheroid formation in colorectal cancer (2021)
  • Author(s): Akabane Shintaro、Oue Naohide、Sekino Yohei、Asai Ryuichi、Thang Pham Quoc、Taniyama Daiki、Sentani Kazuhiro、Yukawa Masashi、Toda Takashi、Kimura Ken‐ichi、Egi Hiroyuki、Shimizu Wataru、Ohdan Hideki、Yasui Wataru
  • Journal Title: Pathology International Volume: 71 Issue: 7 Pages: 441-452
  • DOI: 10.1111/pin.13098
  • Peer Reviewed / Open Access
• [Journal Article] Peritoneal lavage with hydrogen-rich saline can be an effective and practical procedure for acute peritonitis. (2021)
  • Author(s): Sada H, Egi H, Ide K, Sawada H, Sumi Y, Hattori M, Sentani K, Oue N, Yasui W, Ohdan H
  • Journal Title: Surg Today Volume: - Issue: 11 Pages: 1860-1871
  • DOI: 10.1007/s00595-021-02271-z
  • Peer Reviewed
• [Journal Article] BUB1B Overexpression Is an Independent Prognostic Marker and Associated with CD44, p53, and PD-L1 in Renal Cell Carcinoma. (2021)
  • Author(s): Sekino Y, Han X, Kobayashi G, Babasaki T, Miyamoto S, Kobatake K, Kitano H, Ikeda K, Goto K, Inoue S, Hayashi T, Teishima J, Sakamoto N, Sentani K, Oue N, Yasui W, Matsubara A
  • Journal Title: Oncology Volume: - Issue: 4 Pages: 240-250
  • DOI: 10.1159/000512446
  • Peer Reviewed / Open Access
• [Journal Article] Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns (2021)
  • Author(s): Sentani K, Imai T, Kobayashi G, Hayashi T, Sasaki N, Oue N, Yasui W
  • Journal Title: Gastric Cancer Volume: 24 Issue: 2 Pages: 368-381
  • DOI: 10.1007/s10120-020-01133-w
  • NAID: 40022501535
  • Peer Reviewed / Open Access
• [Presentation] 胃癌の分子生物学的研究と病理診断への応用 (2022)
  • Author(s): 大上直秀
  • Organizer: 第32回佐伯医学会総会
  • Invited
• [Presentation] 消化管癌の分子生物学的研究と病理診断への応用 (2022)
  • Author(s): 大上直秀
  • Organizer: 第14回消化器リサーチセミナー
  • 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/