Development of invasion and/or metastasis of pancreatic and lung cancers by controlling S100A4

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590452
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tohoku University
• Principal Investigator: HORII Akira 東北大学, 医学(系)研究科(研究院), 教授 (40249983)
• Project Period (FY): 2011 – 2013
• Keywords: S100A4 / 膵癌 / 肺癌 / 神経浸潤 / 薬剤耐性

Research Abstract

Overexpression of S100A4 is frequently found in pancreatic and lung cancers. Knockdown suppresses cell growth and forced expression promotes cell motility in both of the cancer types. Furthermore, we analyzed primary resected pancreatic cancer tissues immunohistochemically and found positive association between overexpression of S100A4 and tumor cell invasion, particularly to nerves. Microarray analyses after forced expression in S100A4-low expressing cells identified candidate downstream genes and we are now analyzing functions of these genes.
Because overexpression of S100A4 and poor prognoses after gemcitabine treatment was reported in pancreatic cancer, we established 8 cancer cell lines with acquired gemcitabine resistance; these include four pancreatic, one gastric, one colon, one gallbladder, one bile duct cancers. Frequent inactivating mutation in deoxycytidine kinase was observed, and further investigation is on the way.

Research Products

• [Journal Article] Characterization of functional transient receptor potential melastatin 8 (TRPM8) channels in human pancreatic ductal adenocarcinoma cells (2014)
  • Author(s): Cucu D, Chiritoiu G, Petrescu S, Babes A, Stanica L, Duda DG, Horii A, Dima SO, Popescu I
  • Journal Title: Pancreas Volume: (in press)
  • DOI: 10.1097/MPA.0000000000000106
  • Peer Reviewed
• [Journal Article] S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility (2014)
  • Author(s): Chen N, Sato D, Saiki Y, Sunamura M, Fukushige S, Horii A
  • Journal Title: Biochem Biophys Res Commun Volume: 447 Pages: 459-464
  • DOI: 10.1016/j.bbrc.2014.04.025
  • Peer Reviewed
• [Journal Article] Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers (2014)
  • Author(s): Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, Manachai N, Yamakawa N, Hamasaki M, Kitabayashi I, Arai Y, Kanai Y, Taki T, Abe T, Kiyonari H, Shimoda K, Ohshima K, Horii A, Shima H, Taniwaki M, Yamaguchi R, Morishita K
  • Journal Title: Nat Commun Volume: 5 Pages: 3393
  • DOI: 10.1038/ncomms4393
  • Peer Reviewed
• [Journal Article] Molecular pathology of pancreatic cancer (2014)
  • Author(s): Saiki Y, Horii A
  • Journal Title: Pathol Int Volume: 64 Pages: 10-19
  • DOI: 10.1111/pin.12114
• [Journal Article] Road to early detection of pancreatic cancer : attempts to utilize epigenetic biomarkers (2014)
  • Author(s): Fukushige S, Horii A
  • Journal Title: Cancer Lett Volume: 342 Pages: 231-237
  • DOI: 10.1016/j.canlet.2012.03.022
  • Peer Reviewed
• [Journal Article] Suppressed expression of NDRG2 correlates with poor prognosis in pancreatic cancer (2013)
  • Author(s): Yamamura A, Miura K, Karasawa H, Morishita K, Abe K, Mizuguchi Y, Saiki Y, Fukushige S, Kaneko N, Sase T, Nagase H, Sunamura M, Motoi F, Egawa S, Shibata C, Unno M, Sasaki I, Horii A
  • Journal Title: Biochem Biophys Res Commun Volume: 441 Pages: 102-107
  • DOI: 10.1016/j.bbrc.2013.10.010
  • Peer Reviewed
• [Journal Article] p190A RhoGAP is involved in EGFR pathways and promotes proliferation, invasion and migration in lung adenocarcinoma cells (2013)
  • Author(s): Notsuda H, Sakurada A, Endo C, Okada Y, Horii A, Shima H, Kondo T
  • Journal Title: Int J Oncol Volume: 43 Pages: 1569-1577
  • DOI: 10.3892/ijo.2013.2096
  • Peer Reviewed
• [Journal Article] DNA methylation in cancer : A gene silencing mechanism and the clinical potential of its biomarkers (2013)
  • Author(s): Fukushige S, Horii A
  • Journal Title: Tohoku J Exp Med Volume: 229 Pages: 173-185
  • DOI: 10.1620/tjem.229.173
• [Journal Article] The expression of S100A4 in human pancreatic cancer is associated with invasion (2013)
  • Author(s): Tsukamoto N, Egawa S, Akada M, Abe K, Saiki Y, Kaneko N, Yokoyama S, Shima K, Yamamura A, Motoi F, Abe H, Hayashi H, Ishida K, Moriya T, Tabata T, Kondo E, Kanai N, Gu Z, Sunamura M, Unno M, Horii A
  • Journal Title: Pancreas Volume: 42 Pages: 1027-1033
  • DOI: 10.1097/MPA.0b013e31828804e7
  • Peer Reviewed
• [Journal Article] Proposal of screening method for intestinal mucus adhesive lactobacilli using the enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (2013)
  • Author(s): Kinoshita H, Imoto S, Suda Y, Ishida M, Watanabe M, Kawai Y, Kitazawa H, Miura K, Horii A, Saito T
  • Journal Title: Anim Sci J Volume: 84 Pages: 150-158
  • DOI: 10.1111/j.1740-0929.2012.01054.x
  • Peer Reviewed
• [Journal Article] New screening methods for probiotics with adhesion properties to sialic acid and sulfate residues in human colonic mucin using the Biacore assay (2013)
  • Author(s): Huang I-N, Okawara, T, Watanabe M, Kawai Y, Kitazawa H, Ohnuma S, Shibata C, Horii A, Kimura K, Taketomo N, Xiao J, Iwatsuki K, Saito T
  • Journal Title: J Appl Microbiol Volume: 114 Pages: 854-860
  • DOI: 10.1111/jam.12063
  • Peer Reviewed
• [Journal Article] S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cancer cells (2012)
  • Author(s): Sekine H, Chen N, Sato K, Saiki Y, Yoshino Y, Umetsu Y, Jin G, Nagase H, Gu Z, Fukushige S, Sunamura M, Horii A
  • Journal Title: Biochem Biophys Res Commun Volume: 429 Pages: 214-219
  • DOI: 10.1016/j.bbrc.2012.10.048
  • Peer Reviewed
• [Journal Article] An adhesin-like protein, Lam29, from Lactobacillus mucosae ME-340 binds to histone H3 and blood group antigens in human colonic mucus (2012)
  • Author(s): Watanabe M, Kinoshita H, Huang IN, Eguchi K, Tsurumi T, Kawai Y, Kitazawa H, Kimura K, Taketomo N, Kikuchi D, Sase T, Miura K, Ogawa H, Shibata C, Horii A, Saito T
  • Journal Title: Biosci Biotechnol Biochem. Volume: 76 Pages: 1655-1660
  • DOI: 10.1271/bbb.120150
  • Peer Reviewed
• [Journal Article] Potential utility of eGFP-expressing NOG mice (NOG-EGFP) as a high purity cancer sampling system (2012)
  • Author(s): Shima K, Mizuma M, Hayashi H, Nakagawa K, Okada T, Sakata N, Omura N, Kitamura Y, Motoi F, Rikiyama T, Katayose Y, Egawa S, Ishii N, Horii A, Unno M
  • Journal Title: J Exp Clin Cancer Res Volume: 31 Pages: 55
  • DOI: 10.1186/1756-9966-31-55
  • Peer Reviewed
• [Journal Article] miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis (2012)
  • Author(s): Ogawa T, Saiki Y, Shiga K, Chen N, Fukushige S, Sunamura M, Nagase H, Hashimoto S, Matsuura K, Saijo S, Kobayashi T, Horii A
  • Journal Title: Cancer Sci Volume: 103 Pages: 1737-1743
  • DOI: 10.1111/j.1349-7006.2012.02338.x
  • Peer Reviewed
• [Journal Article] DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells (2012)
  • Author(s): Saiki Y, Yoshino Y, Fujimura H, Manabe T, Kudo Y, Shimada M, Mano N, Nakano T, Lee Y, Shimizu S, Oba S, Fujiwara S, Shimizu H, Chen N, Nezhad ZK, Jin G, Fukushige S, Sunamura M, Ishida M, Motoi F, Egawa S, Unno M, Horii A
  • Journal Title: Biochem Biophys Res Commun Volume: 421 Pages: 98-104
  • DOI: 10.1016/j.bbrc.2012.03.122
  • Peer Reviewed
• [Journal Article] Methylation of death-associated protein kinase (DAPK) is associated with cetuximab and erlotinib resistance (2012)
  • Author(s): Ogawa T, Liggett TE, Melnikov AA, Monitto CL, Kusuke D, Shiga K, Kobayashi T, Horii A, Chattejee A, Levenson VV, Koch W, Sidransky D, Chang X
  • Journal Title: Cell Cycle Volume: 11 Pages: 1655-1662
  • DOI: 10.4161/cc.20120
  • Peer Reviewed
• [Journal Article] A human head and neck squamous cell carcinoma cell line with acquired cis-diamminedichloroplatinum-resistance shows remarkable upregulation of BRCA1 and hypersensitivity to taxane (2011)
  • Author(s): Saiki Y, Ogawa T, Shiga K, Sunamura M, Kobayashi T, Horii A
  • Journal Title: Int J Otolaryngol Volume: 52 Pages: 1852
  • DOI: 10.1155/2011/521852
  • Peer Reviewed
• [Journal Article] Identification of epigenetically silenced genes in human pancreatic cancer by a novel method"microarray coupled with methyl-CpG targeted transcriptional activation"(MeTA-array) (2011)
  • Author(s): Shimizu H, Horii A, Sunamura M, Motoi F, Egawa S, Unno M, Fukushige S
  • Journal Title: Biochem Biophys Res Commun Volume: 411 Pages: 162-167
  • DOI: 10.1016/j.bbrc.2011.06.121
  • Peer Reviewed
• [Journal Article] Microarray coupled with methyl-CpG targeted transcriptional activation (MeTA-array) identifies hypermethylated genes containing the stringent criteria of CpG islands at high frequency (2011)
  • Author(s): Sato Y, Horii A, Fukushige S
  • Journal Title: Epigenetics Volume: 6 Pages: 752-759
  • DOI: 10.4161/epi.6.6.15906
  • Peer Reviewed
• [Presentation] IFI27 and NOV, downstream regulated genes by S100A4, are playing important roles in pancreatic carcinogenesis (2014)
  • Author(s): Chen N, Saiki Y, Sekine H, Sunamura M, Fukushige S, Motoi F, Egawa S, Unno M, Horii A
  • Organizer: アメリカ癌学会
  • Place of Presentation: アメリカ・サンディエゴ
  • Year and Date: 20140405-09
• [Presentation] TET oxidase activity accumulated on methyl-CpG sites extensively upregulates methylated genes through DNA demethylation (2014)
  • Author(s): Fukushige S, Mizuguchi Y Horii A
  • Organizer: アメリカ癌学会
  • Place of Presentation: アメリカ・サンディエゴ
  • Year and Date: 20140405-09
• [Presentation] IFI27 and NOV, downstream regulated genes by S100A4, are playing important roles in pancreatic carcinogenesis (2013)
  • Author(s): Chen N, Saiki Y, Sunamura M, Fukushige S, Motoi F, Egawa S, Unno M, Horii A
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 20131003-05
• [Presentation] Chemosensitivity prediction by microRNA profiling in head and neck and esophageal squamous cell carcinoma (2013)
  • Author(s): Saiki Y, Ogawa T, Nakano T, Chen N, Sunamura M, Horii A
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 20131003-05
• [Presentation] TET1 hydroxylase activity reactivates the expression of epigenetically silenced genes (2013)
  • Author(s): Fukushige S, Mizuguchi Y, Horii A
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 20131003-05
• [Presentation] マイクロRNAによる抗がん剤感受性予測 (2013)
  • Author(s): 斎木由利子、中野智太、小川武則、砂村眞琴、永瀬浩喜、堀井明
  • Organizer: 日本癌病態治療研究会
  • Place of Presentation: 東京
  • Year and Date: 20130627-28
• [Presentation] MeTA-array, a useful method to identify genes transcriptionally silenced by tumor-specific hypermethylation in cancer (2013)
  • Author(s): Fukushige S, Horii A
  • Organizer: アメリカ癌学会
  • Place of Presentation: アメリカ・ワシントン
  • Year and Date: 20130406-10
• [Presentation] Suppressed NDRG2 expression correlates with poor prognosis in pancreatic cancer, and suppression mechanism is different from colorectal and gastric cancer (2013)
  • Author(s): Mizuguchi Y, Yamamura A, Miura K, Karasawa H, Morishita K, Abe K, Saiki Y, Fukushige S, Kaneko N, Sase T, Motoi F, Egawa S, Shibata C, Unno M, Sasaki I, Horii A
  • Organizer: 日本癌学会-アメリカ癌学会合同会議
  • Place of Presentation: アメリカ・マウイ島
  • Year and Date: 20130221-25
• [Presentation] ゲムシタビン耐性ヒト癌細胞株におけるdeoxycytidine kinaseの不活化 (2012)
  • Author(s): 齋木由利子、吉野優樹、福重真一、砂村真琴、石田晶玄、元井冬彦、江川新一、海野倫明、堀井明
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌
  • Year and Date: 20120919-21
• [Presentation] ヒト癌において腫瘍特異的な高度メチル化により転写抑制された遺伝子のMeTA-arrayによる効率的探索法の開発 (2012)
  • Author(s): 福重真一、堀井明
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌
  • Year and Date: 20120919-21
• [Presentation] miR-34a発現低下は鼻副鼻腔癌におけるシスプラチン化学療法の予後規定因子である (2012)
  • Author(s): 小川武則、齋木由利子、志賀清人、松浦一登、加藤健吾、西條茂、小林俊光、福重真一、堀井明
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌
  • Year and Date: 20120919-21
• [Presentation] Road to early detection and curative treatment of pancreatic cancer (2012)
  • Author(s): Horii A
  • Organizer: Academician Nicolae Cajalシンポジウム
  • Place of Presentation: ルーマニア・ブカレスト
  • Year and Date: 20120328-30
• [Presentation] ゲムシタビン耐性膵癌細胞株におけるゲムシタビン代謝の解析 (2011)
  • Author(s): 齋木由利子、江川新一、砂村眞琴、海野倫明、堀井明
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 20111003-05
• [Presentation] メチルCpG配列を標的とする転写活性化とマイクロアレイの組み合わせはヒトがんにおける低メチル化遺伝子の同定を可能にする (2011)
  • Author(s): 福重真一、陳娜、堀井明
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 20111003-05
• [Presentation] NOG-EGFPマウス異種移植モデルを用いた高精度な癌細胞sampling systemの構築を目指して (2011)
  • Author(s): 嶋健太郎、水間正道、大村範幸、林洋毅、中川圭、岡田恭穂、北村洋、元井冬彦、力山敏樹、片寄友、江川新一、石井直人、堀井明、海野倫明
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 20111003-05
• [Presentation] New prevention strategy for inflammatory bowel disease using probiotic lactic acid bacteria and/or Bifidobacterium with specific adhesion to human intestine (2011)
  • Author(s): Saito T, Yukishita R, Watanabe M, Katazawa H, Kawai Y, Horii A, Ikezawa F, Yamamura A, Ogawa H, Miura K, Shibata C, Sasaki I
  • Organizer: Lactic Acid Bacteriaシンポジウム
  • Place of Presentation: ニュージーランド・エグモントアーンゼー
  • Year and Date: 20110828-0901
• [Presentation] 膵癌のGemcitabine耐性機構の解明 (2011)
  • Author(s): 齋木由利子、江川新一、海野倫明、砂村眞琴、堀井明
  • Organizer: 日本膵臓学会
  • Place of Presentation: 弘前
  • Year and Date: 20110729-30
• [Presentation] Each methyl-CpG binding domain has the ability to target different methylated genes in human cancer (2011)
  • Author(s): Fukushige S, Horii A
  • Organizer: アメリカ癌学会
  • Place of Presentation: アメリカ・オーランド
  • Year and Date: 20110402-06
• [Remarks]
  • URL: http://www.med.tohoku.ac.jp/org/medical/13/index.html
• [Remarks]
  • URL: http://www.molpath.med.tohoku.ac.jp/index.html