消化管癌の分子分類別にみた超保存領域T-UCRの生物学的意義と臨床応用

2019 Fiscal Year Research-status Report

• Project/Area Number: 19K07434
• Research Institution: Hiroshima University
• Principal Investigator: 仙谷 和弘 広島大学, 医系科学研究科(医), 講師 (30508164)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: T-UCR / 癌幹細胞

Outline of Annual Research Achievements

本年度は、癌における転写超保存領域T-UCRの意義を明らかにするため、消化管癌と同様、代表的な癌の一つである膀胱癌におけるUc.63+の意義に関する解析を行った。定量的RT-PCR法による検討ではUc.63+は尿路上皮癌で高発現しており、その発現増加が増殖能を亢進させること、逆に発現低下がアンドロゲン陽性尿路上皮癌細胞株においてシスプラチン感受性を亢進させることを明らかとした。また、胃癌の癌幹細胞マーカー探索のために行ったspheroid colony formationにより同定したclaspinが免疫組織化学的に203例中94例(47%)に発現し、T因子、N 因子、ステージの高い症例や脈管侵襲のある症例ほど高発現すること、独立した予後不良因子であるとともにsiRNAを用いた解析によりその発現が増殖能や浸潤能を制御すること、さらにその発現は既存の癌幹細胞マーカーであるCD44に加えて受容体型チロシンキナーゼであるHER2やp53とも有意な相関関係にあることを明らかとし、胃癌の進展や癌幹細胞を制御する重要な癌関連分子であることを示した。腎細胞癌においてもclaspinは95例中45例(47%)に発現し、T因子、ステージの高い症例や脈管侵襲のある症例、組織学的異型度の高い症例ほど高発現すること、ErkやAktのリン酸化を通じて増殖能を制御すること、CD44、EGFR、p53に加えて免疫チェックポイントに関わるPD-L1とも有意な相関を示し、重要な治療標的分子となりうる可能性が示された。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

現在までに本研究の解析に必要な消化管癌および他臓器の癌を含むヒト悪性腫瘍における組織サンプルを十分収集できており、実際にT-UCRs発現解析データに基づく候補の検証を行っている。本年度解析したUc.63+以外の検討も他臓器由来の癌などで行っており、T-UCRの解析を実際のヒト消化管癌のサンプルを用いてその 意義について検証する作業は、おおむね順調に進展しているものと考えられる。

Strategy for Future Research Activity

消化管癌におけるT-UCRの発現と分子機構を解明するため、引き続き本年度と同様の解析を行うとともに、多数の臨床検体を用いた臨床病理学的検討、さらには 関連分子の検討などを行い、治療標的分子、血清腫瘍マーカー、鑑別診断マーカー等の開発につなげる予定である。

Causes of Carryover

令和元年度は主にデータ解析や文献検索等を通じて候補分子の選定を行うことに専念したため、次年度使用額が生じた。次年度以降は、令和元年度に選定した候補分子の臨床病理学的意義を明らかにするため、多数の臨床検体を用いた臨床病理学的検討、さらには 関連分子の検討など、治療標的分子、血清腫瘍マーカー、鑑別診断マーカー等の開発につなげる予定であり、次年度使用額と合わせて研究に必要な試薬や抗体を購入する予定である。

Research Products

• [Journal Article] PTEN Is Involved in Sunitinib and Sorafenib Resistance in Renal Cell Carcinoma. (2020)
  • Author(s): Sekino Y, Hagura T, Han X, Babasaki T, Goto K, Inoue S, Hayashi T, Teishima J, Shigeta M, Taniyama D, Kuraoka K, Sentani K, Yasui W, Matsubara A.
  • Journal Title: Anticancer Res. Volume: 40 Pages: 1943-1951
  • DOI: 10.21873/anticanres.14149.
  • Peer Reviewed
• [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: - Pages: -
  • DOI: 10.1016/j.urolonc.2020.02.010.
  • Peer Reviewed
• [Journal Article] Impact of radiological morphology of clinical T1 renal cell carcinoma on the prediction of upstaging to pathological T3. (2020)
  • Author(s): Teishima J, Hayashi T, Kitano H, Sadahide K, Sekino Y, Goto K, Inoue S, Honda Y, Sentani K, Awai K, Yasui W, Matsubara A.
  • Journal Title: Jpn J Clin Oncol. Volume: - Pages: -
  • DOI: 10.1093/jjco/hyz154.
  • Peer Reviewed
• [Journal Article] Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction. (2020)
  • Author(s): Kobatake K, Ikeda KI, Nakata Y, Yamasaki N, Ueda T, Kanai A, Sentani K, Sera Y, Hayashi T, Koizumi M, Miyakawa Y, Inaba T, Sotomaru Y, Kaminuma O, Ichinohe T, Honda ZI, Yasui W, Horie S, Black PC, Matsubara A, Honda H.
  • Journal Title: Clin Cancer Res. Volume: - Pages: -
  • DOI: 10.1158/1078-0432.CCR-19-2230.
  • Peer Reviewed / Int'l Joint Research
• [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 Pages: 1020-1027
  • DOI: 10.1111/cas.14299.
  • Peer Reviewed / Open Access
• [Journal Article] Annexin A10 is involved in the induction of pancreatic duodenal homeobox-1 in gastric cancer tissue, cells and organoids. (2020)
  • Author(s): Ishikawa A, Sakamoto N, Honma R, Taniyama D, Fukada K, Hattori T, Sentani K, Oue N, Yanagihara K, Tanabe K, Ohdan H, Yasui W.
  • Journal Title: Oncol Rep. Volume: 43 Pages: 581-590
  • DOI: 10.3892/or.2019.7422.
  • Peer Reviewed
• [Journal Article] Magnetic resonance imaging/transrectal ultrasonography fusion targeted prostate biopsy finds more significant prostate cancer in biopsy-naive Japanese men compared with the standard biopsy. (2020)
  • Author(s): Fujii S, Hayashi T, Honda Y, Terada H, Akita R, Kitamura N, Ueda E, Han X, Ueno T, Miyamoto S, Kitano H, Inoue S, Teishima J, Abdi H, Awai K, Takeshima Y, Sentani K, Yasui W, Matsubara A.
  • Journal Title: Int J Urol. Volume: 27 Pages: 140-146
  • DOI: 10.1111/iju.14149.
  • Peer Reviewed
• [Journal Article] Clinical staging of upper urinary tract urothelial carcinoma for T staging: Review and pictorial essay. (2019)
  • Author(s): Honda Y, Nakamura Y, Teishima J, Goto K, Higaki T, Narita K, Akagi M, Terada H, Kaichi Y, Fujii S, Hayashi T, Matsubara A, Sentani K, Yasui W, Iida M, Awai K.
  • Journal Title: Int J Urol. Volume: 26 Pages: 1024-1032
  • DOI: 10.1111/iju.14068.
  • Peer Reviewed
• [Journal Article] Synbiotics suppress colitis-induced tumorigenesis in a colon-specific cancer mouse model. (2019)
  • Author(s): Saito Y, Hinoi T, Adachi T, Miguchi M, Niitsu H, Kochi M, Sada H, Sotomaru Y, Sakamoto N, Sentani K, Oue N, Yasui W, Tashiro H, Ohdan H.
  • Journal Title: PLoS One. Volume: 14 Pages: e0216393
  • DOI: 10.1371/journal.pone.0216393.
  • Peer Reviewed / Open Access
• [Journal Article] Helicobacter suis infection is associated with nodular gastritis-like appearance of gastric mucosa-associated lymphoid tissue lymphoma. (2019)
  • Author(s): Takigawa H, Masaki S, Naito T, Yuge R, Urabe Y, Tanaka S, Sentani K, Matsuo T, Matsuo K, Chayama K, Kitadai Y.
  • Journal Title: Cancer Med. Volume: 8 Pages: 4370-4379
  • DOI: 10.1002/cam4.2314.
  • Peer Reviewed / Open Access
• [Journal Article] miR-130b Promotes Sunitinib Resistance through Regulation of PTEN in Renal Cell Carcinoma. (2019)
  • Author(s): Sekino Y, Sakamoto N, Sentani K, Oue N, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Oncology. Volume: 97 Pages: 164-172
  • DOI: 10.1159/000500605.
  • Peer Reviewed
• [Journal Article] CD204-Positive Tumor-associated Macrophages Relate to Malignant Transformation of Colorectal Adenoma. (2019)
  • Author(s): Taniyama D, Taniyama K, Kuraoka K, Yamamoto H, Zaitsu J, Saito A, Sakamoto N, Sentani K, Oue N, Yasui W.
  • Journal Title: Anticancer Res. Volume: 39 Pages: 2767-2775
  • DOI: 10.21873/anticanres.13403.
  • Peer Reviewed
• [Journal Article] SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival. (2019)
  • Author(s): Shigematsu Y, Oue N, Sekino Y, Sakamoto N, Sentani K, Uraoka N, Hayashi T, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Pathobiology. Volume: 86 Pages: 208-216
  • DOI: 10.1159/000497206.
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of 5015 Salivary Gland Neoplasms Registered in the Hiroshima Tumor Tissue Registry over a Period of 39 Years. (2019)
  • Author(s): Sentani K, Ogawa I, Ozasa K, Sadakane A, Utada M, Tsuya T, Kajihara H, Yonehara S, Takeshima Y, Yasui W.
  • Journal Title: J Clin Med. Volume: 8 Pages: E566
  • DOI: 10.3390/jcm8050566.
  • 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: 24 Pages: 771-778
  • DOI: 10.1007/s10147-019-01443-9.
  • Peer Reviewed
• [Journal Article] Deficiency of Stomach-Type Claudin-18 in Mice Induces Gastric Tumor Formation Independent of H pylori Infection. (2019)
  • Author(s): Suzuki K, Sentani K, Tanaka H, Yano T, Suzuki K, Oshima M, Yasui W, Tamura A, Tsukita S.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 8 Pages: 119-142
  • DOI: 10.1016/j.jcmgh.2019.03.003.
  • Peer Reviewed / Open Access
• [Journal Article] Transcribed ultraconserved region Uc.63+ promotes resistance to cisplatin through regulation of androgen receptor signaling in bladder cancer. (2019)
  • Author(s): Sekino Y, Sakamoto N, Ishikawa A, Honma R, Shigematsu Y, Hayashi T, Sentani K, Oue N, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Oncol Rep. Volume: 41 Pages: 3111-3118
  • DOI: 10.3892/or.2019.7039.
  • 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 Pages: E225
  • DOI: 10.3390/jcm8020225.
  • Peer Reviewed / Open Access
• [Journal Article] Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients. (2019)
  • Author(s): Sekino Y, Oue N, Mukai S, Shigematsu Y, Goto K, Sakamoto N, Sentani K, Hayashi T, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Prostate. Volume: 79 Pages: 234-242
  • DOI: 10.1002/pros.23728.
  • Peer Reviewed
• [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 Pages: 430-442
  • DOI: 10.1111/his.13764.
  • Peer Reviewed
• [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
• [Presentation] Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer. (2019)
  • Author(s): Sentani K, Kobayashi G, Imai T, Sakamoto N, Kuraoka K, Oue N, Sasaki N, Taniyama K and Yasui W
  • Organizer: The 31st European Congress of Pathology
  • Int'l Joint Research
• [Presentation] 広島県腫瘍登録事業に基づく5015例の唾液腺腫瘍の臨床病理学的特徴． (2019)
  • Author(s): 仙谷和弘、小川郁子、梶原博毅、米原修治、武島幸男、安井 弥
  • Organizer: 第108回日本病理学会総会
• [Presentation] 広島県腫瘍登録事業に基づく5015例の唾液腺腫瘍の臨床病理学的特徴． (2019)
  • Author(s): 仙谷和弘、小川郁子、梶原博毅、武島幸男、安井 弥
  • Organizer: 第78回日本癌学会学術総会
• [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/