消化管癌の組織学的多様性と超保存領域T-UCRからみた分子機構の解明と診断応用

2016 Fiscal Year Research-status Report

• Project/Area Number: 16K08691
• Research Institution: Hiroshima University
• Principal Investigator: 仙谷 和弘 広島大学, 医歯薬保健学研究院(医), 講師 (30508164)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: T-UCR / Uc.160+ / SPC18

Outline of Annual Research Achievements

消化管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、本年度はヒト胃癌で発現低下が報告されているUc.160+について胃癌における発現と機能解析を行った。定量的RT-PCR法による検討では非癌部と比較して癌部ではUc.160+の発現低下が見られ、ヒト胃癌組織標本におけるin situ hybridizationによる検討でも同様の結果が認められた。バイサルファイトシークエンス法によってUc.160+の発現低下はDNAメチル化によることを示し、更にUc.160+はPTENの発現を調節することによってAktのリン酸化を抑制することも明らかにした。
また、網羅的遺伝子発現解析によって見出されたSignal peptidase complex 18 (SPC18)が大腸癌の58%に発現し、N因子、stageの高いものほど高発現することから腫瘍進展との関連や予後不良と相関することを見出したが、生物学的機能解析によりSPC18の発現がEGFR, Erk, Aktのリン酸化と関連することが判明した。免疫組織化学的解析によりSPC18の腫瘍内局在は特に大腸癌の浸潤先進部に多いことがわかり、β-cateninの核内集積やMMP7の発現と有意に相関することも明らかにした。更に大腸の前癌性病変の検討により、SPC18は通常型のadenoma-carcinoma pathwayから発生する大腸癌と深く関わり、serrated pathwayを経る大腸癌ではSPC18の陽性率が高くないことも示した。

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.160+は胃癌において発現の低下が見られ、その原因としてメチル化の関与を含む分子機構の一端が明らかになったことから治療標的としての応用も期待される。複数の候補となる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に、引き続き本年度と同様の解析を行うとともに、細胞株を用いたspheroid形成等の形態学的変化の観察や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。

Research Products

• [Journal Article] Characteristic expression of fukutin in gastric cancer among atomic bomb survivors. (2017)
  • Author(s): Pham TT, Oue N, Yamamoto M, Fujihara M, Ishida T, Mukai S, Sakamoto N, Sentani K, Yasui W.
  • Journal Title: Oncol Lett Volume: 13 Pages: 937-941
  • DOI: 10.3892/ol.2016.5520.
  • Peer Reviewed / Open Access
• [Journal Article] Long-term follow-up study of gastric adenoma; tumor-associated macrophages are associated to carcinoma development in gastric adenoma. (2017)
  • Author(s): Taniyama D, Taniyama K, Kuraoka K, Zaitsu J, Saito A, Nakatsuka H, Sakamoto N, Sentani K, Oue N, Yasui W.
  • Journal Title: Gastric Cancer Volume: 20 Pages: 929-939
  • DOI: 10.1007/s10120-017-0713-x.
  • Peer Reviewed
• [Journal Article] BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. (2017)
  • Author(s): Sakamoto N, Feng Y, Stolfi C, Kurosu Y, Green M, Lin J, Green ME, Sentani K, Yasui W, McMahon M, Hardiman KM, Spence JR, Horita N, Greenson JK, Kuick R, Cho KR, Fearon ER.
  • Journal Title: Elife Volume: 10 Pages: 6
  • DOI: 10.7554/eLife.20331.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression. (2017)
  • Author(s): Hattori T, Sentani K, Naohide O, Sakamoto N, Yasui W.
  • Journal Title: Cancer Sci Volume: 108 Pages: 143-150
  • DOI: 10.1111/cas.13121.
  • Peer Reviewed / Open Access
• [Journal Article] KIFC1 induces resistance to docetaxel and is associated with survival of patients with prostate cancer. (2017)
  • Author(s): Sekino Y, Oue N, Shigematsu Y, Ishikawa A, Sakamoto N, Sentani K, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Urol Oncol Volume: 35 Pages: 13-31
  • DOI: 10.1016/j.urolonc.2016.08.007.
  • Peer Reviewed
• [Journal Article] Overexpression of KIF11 in Gastric Cancer with Intestinal Mucin Phenotype. (2017)
  • Author(s): Imai T, Oue N, Nishioka M, Mukai S, Oshima T, Sakamoto N, Sentani K, Matsusaki K, Yoshida K, Yasui W.
  • Journal Title: Pathobiology Volume: 84 Pages: 16-24
  • DOI: 10.1159/000447303.
  • Peer Reviewed
• [Journal Article] Regeneration of rat corpora cavernosa tissue by transplantation of CD133+ cells derived from human bone marrow and placement of biodegradable gel sponge sheet. (2017)
  • Author(s): Inoue S, Miyamoto K, Shinmei S, Shoji K, Teishima J, Sentani K, Yasui W, Matsubara A.
  • Journal Title: Asian J Androl Volume: 19 Pages: 203-207
  • DOI: 10.4103/1008-682X.179155.
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of Transmembrane Protein BST2 is Associated with Poor Survival of Patients with Esophageal, Gastric, or Colorectal Cancer. (2017)
  • Author(s): Mukai S, Oue N, Oshima T, Mukai R, Tatsumoto Y, Sakamoto N, Sentani K, Tanabe K, Egi H, Hinoi T, Ohdan H, Yasui W.
  • Journal Title: Ann Surg Oncol Volume: 24 Pages: 594-602
  • DOI: 10.1245/s10434-016-5100-z.
  • Peer Reviewed
• [Journal Article] KIF11 Is Required for Spheroid Formation by Oesophageal and Colorectal Cancer Cells. (2017)
  • Author(s): Imai T, Oue N, Sentani K, Sakamoto N, Uraoka N, Egi H, Hinoi T, Ohdan H, Yoshida K, Yasui W.
  • Journal Title: Anticancer Res. Volume: 37 Pages: 47-55
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gasdermin C Is Upregulated by Inactivation of Transforming Growth Factor β Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation. (2016)
  • Author(s): Miguchi M, Hinoi T, Shimomura M, Adachi T, Saito Y, Niitsu H, Kochi M, Sada H, Sotomaru Y, Ikenoue T, Shigeyasu K, Tanakaya K, Kitadai Y, Sentani K, Oue N, Yasui W, Ohdan H.
  • Journal Title: PLoS One. Volume: 11 Pages: 0166422
  • DOI: 10.1371/journal.pone.0166422.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinicopathologic characteristics and management of minute esophageal lesions diagnosed by narrow-band imaging endoscopy. (2016)
  • Author(s): Kumamoto T, Sentani K, Oka S, Tanaka S, Yasui W.
  • Journal Title: Endosc Int Open. Volume: 4 Pages: 927-932
  • DOI: 10.1055/s-0042-110788.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intrahepatic cholangiocarcinoma coinciding with a liver metastasis from a rectal carcinoma: a case report. (2016)
  • Author(s): Akabane S, Ohira M, Kobayashi T, Kuroda S, Tanimine N, Shimizu S, Tahara H, Ide K, Ishiyama K, Egi H, Tanabe K, Sentani K, Yasui W, Ohdan H.
  • Journal Title: Surg Case Rep. Volume: 2 Pages: 94
  • DOI: 10.1186/s40792-016-0222-x.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pure invasive micropapillary carcinoma of the esophagogastric junction with lymph nodes and liver metastasis. (2016)
  • Author(s): Hattori T, Sentani K, Hattori Y, Oue N, Yasui W.
  • Journal Title: Pathol Int. Volume: 66 Pages: 583-586
  • DOI: 10.1111/pin.12450.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer. (2016)
  • Author(s): Niitsu H, Hinoi T, Kawaguchi Y, Sentani K, Yuge R, Kitadai Y, Sotomaru Y, Adachi T, Saito Y, Miguchi M, Kochi M, Sada H, Shimomura M, Oue N, Yasui W, Ohdan H.
  • Journal Title: Oncogenesis. Volume: 15 Pages: 253
  • DOI: 10.1038/oncsis.2016.47.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased Calcineurin A Expression Is Associated with a Lower Relapse-Free Survival Rate after Colorectal Cancer Surgery. (2016)
  • Author(s): Niitsu H, Hinoi T, Sentani K, Mukai S, Adachi T, Saito Y, Miguchi M, Kochi M, Sada H, Oue N, Yasui W, Ohdan H.
  • Journal Title: Pathobiology. Volume: 83 Pages: 308-315
  • DOI: 10.1159/000445121.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Balloon Cell Malignant Melanoma in a Young Female: A Case Report and Review of the Literature. (2016)
  • Author(s): Hattori Y, Sentani K, Hattori T, Matsuo Y, Kawai M, Shindo H, Tanaka M, Hide M, Yasui W.
  • Journal Title: Case Rep Oncol. Volume: 27 Pages: 262-266
  • DOI: 10.1159/000446065.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of KIFC1 expression in gastric cancer spheroids. (2016)
  • Author(s): Oue N, Mukai S, Imai T, Pham TT, Oshima T, Sentani K, Sakamoto N, Yoshida K, Yasui W.
  • Journal Title: Oncol Rep. Volume: 36 Pages: 349-355
  • DOI: 10.3892/or.2016.4781.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of multidrug resistance 1 expression by CDX2 in ovarian mucinous adenocarcinoma. (2016)
  • Author(s): Koh I, Hinoi T, Sentani K, Hirata E, Nosaka S, Niitsu H, Miguchi M, Adachi T, Yasui W, Ohdan H, Kudo Y.
  • Journal Title: Cancer Med. Volume: 5 Pages: 1546-1555
  • DOI: 10.1002/cam4.697.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A case of tubulocystic carcinoma of the kidney with aggressive features. (2016)
  • Author(s): Maeda Y, Goto K, Honda Y, Kuroda N, Sentani K, Yasui W, Hayashi T, Teishima J, Matsubara A, Nakamura Y, Toyota N, Iida M, Awai K.
  • Journal Title: Jpn J Radiol. Volume: 34 Pages: 307-311
  • DOI: 10.1007/s11604-016-0525-7.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN. (2016)
  • Author(s): Ueda T, Nakata Y, Yamasaki N, Oda H, Sentani K, Kanai A, Onishi N, Ikeda K, Sera Y, Honda ZI, Tanaka K, Sata M, Ogawa S, Yasui W, Saya H, Takita J, Honda H.
  • Journal Title: Oncogene. Volume: 35 Pages: 4447-4458
  • DOI: 10.1038/onc.2015.519.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regression of Cecal MALT Lymphoma after Antibiotic Treatment in a Patient with Helicobacter pylori Infection. (2016)
  • Author(s): Yuge R, Kitadai Y, Tanaka S, Uraoka N, Sentani K, Yasui W, Chayama K.
  • Journal Title: Intern Med. Volume: 55 Pages: 135-139
  • DOI: 10.2169/internalmedicine.55.5937.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation. (2016)
  • Author(s): Goto K, Ishikawa S, Honma R, Tanimoto K, Sakamoto N, Sentani K, Oue N, Teishima J, Matsubara A, Yasui W.
  • Journal Title: Oncogene. Volume: 35 Pages: 3598-3606
  • DOI: 10.1038/onc.2015.445.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras. (2016)
  • Author(s): Kawaguchi Y, Hinoi T, Saito Y, Adachi T, Miguchi M, Niitsu H, Sasada T, Shimomura M, Egi H, Oka S, Tanaka S, Chayama K, Sentani K, Oue N, Yasui W, Ohdan H.
  • Journal Title: J Gastroenterol. Volume: 51 Pages: 447-457
  • DOI: 10.1007/s00535-015-1121-9.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer. (2016)
  • Author(s): Oo HZ, Sentani K, Mukai S, Hattori T, Shinmei S, Goto K, Sakamoto N, Naito Y, Anami K, Trang PT, Yanagihara K, Oue N, Yasui W.
  • Journal Title: Gastric Cancer. Volume: 19 Pages: 443-452
  • DOI: 10.1007/s10120-015-0511-2.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TSPAN8, identified by Escherichia coli ampicillin secretion trap, is associated with cell growth and invasion in gastric cancer. (2016)
  • Author(s): Anami K, Oue N, Noguchi T, Sakamoto N, Sentani K, Hayashi T, Naito Y, Oo HZ, Yasui W.
  • Journal Title: Gastric Cancer. Volume: 19 Pages: 370-380
  • DOI: 10.1007/s10120-015-0478-z.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Histological diversity and clinicopathological significance in mucosal and invasive areas of gastric cancer (2017)
  • Author(s): 仙谷和弘、今井健晴、服部拓也、服部 結、谷山 大樹、石川 洸、山本 悠司、本間りりの、坂本直也、大上直秀、安井 弥
  • Organizer: 第89回日本胃癌学会総会
  • Place of Presentation: 広島
  • Year and Date: 2017-03-08 – 2017-03-10
• [Presentation] CAST法によって同定したFukutinは胃癌の進展に寄与する． (2016)
  • Author(s): 仙谷和弘、Zarni Oo Htoo、向井正一朗、服部拓也、後藤景介、坂本直也、PT Trang、今井健晴、大上直秀、安井 弥
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06 – 2016-10-08
• [Presentation] 広島県腫瘍登録における唾液腺腫瘍の解析. (2016)
  • Author(s): 仙谷和弘、小川郁子、小笹晃太郎、定金敦子、歌田真衣、野間 純、山田博康、津谷隆史、梶原博毅、米原修治、武島幸男、安井 弥
  • Organizer: 地域がん登録全国協議会第25回学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2016-06-02 – 2016-06-03
• [Presentation] CAST法によって同定されたFukutinの腸型粘液形質胃癌における臨床病理学的意義． (2016)
  • Author(s): 仙谷和弘、Htoo Zarni Oo、向井正一朗、服部拓也、後藤景介、坂本直也、Pham Thi Binh Trang、今井健晴、大上直秀、安井 弥
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12 – 2016-05-14
• [Remarks] 広島大学大学院医歯薬保健学研究科分子病理学研究室
  • URL: http://home.hiroshima-u.ac.jp/byori1/index.html