キナーゼ抗体ライブラリーを用いた新規口腔がん治療標的分子の探索

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23390469
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: 本田 一文 独立行政法人国立がん研究センター, 研究所, ユニット長 (10260936)
• Co-Investigator(Kenkyū-buntansha): 森 泰昌 独立行政法人国立がん研究センター, 中央病院, 医員 (00296708) ; 関根 茂樹 独立行政法人国立がん研究センター, 中央病院, 医長 (10321879) ; 平岡 伸介 独立行政法人国立がん研究センター, 中央病院, 医長 (40276217) ; 出雲 俊之 東京医科歯科大学, 歯学部附属病院, 准教授 (80322709) ; 下重 美紀 長崎大学, 医学部, 准教授 (00392340)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: 抗体基盤プロテオミクス / 舌がん / キノーム

Research Abstract

I・II期舌がんに対する組織マイクロアレイを作製し、1000種類以上のモノクローナル抗体を用いて免疫染色を行った。タンパク質の発現状況は国立がん研究センターでインハウスに開発された組織マイクロアレイ抗原発現定量解析ソフトウェア（HistroCaluculator)で患者毎にプロファイルし、口腔がんの転移と予後にかかわるキナーゼ1種類と細胞内骨格タンパク質の同定に成功した。
候補キナーゼは、健常扁平上皮には発現を全く認めなかったが、一部の扁平上皮がんの浸潤先進部で強発現が観察された。強発現する患者の全生存期間は、発現の認められない患者群に比較して、統計学的な有為性を持って短かった。国立がん研究センター中央病院の症例だけでなく、多施設共同研究で検証を行うために、東京歯科大学、東京医科歯科大学の倫理審査委員会に研究申請を行い、東京歯科大学倫理審査委員会から承認を得た。現在、多施設共同研究として検証するために、I-II期舌がんの手術標本の未染色切片を東京歯科大学から収集を行っている。
舌がんの細胞株パネルと細胞株セルアレイを作製し、候補タンパク質のタンパク質発現プロファイルを取得した。舌がん細胞株中で、同キナーゼを強発現する細胞株を見いだし、RNA干渉法を用いて舌がん細胞株による候補タンパク質発現を現弱させて、がん浸潤に対する分子標的としての意義を検討した。

Current Status of Research Progress

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

Reason

研究計画通り、キノーム発現プロファイルの取得は終了した。分子標的キナーゼの同定を終了した。単施設におけるバイアスを排除するための多施設共同研究による検証研究の実施を開始した。標的分子に対する生物学的機能アッセイを開始した。

Strategy for Future Research Activity

当初計画通り、多施設共同研究にて分子標的の臨床的意義を確定する。
生物学的アッセイにて、分子標的の生物学的意義を明らかにする。

Research Products

• [Journal Article] Copy number increase of ACTN4 is a prognostic indicator in salivary gland carcinoma. (2014)
  • Author(s): Watabe Y, Mori T, Yoshimoto S, Nomura T, Shibahara T, Yamada T, Honda K.
  • Journal Title: Cancer Med Volume: Jun;3(3) Pages: 613-22.
  • DOI: 10.1002/cam4.214.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Consistent absence of HER2 expression, regardless of HER2 amplification status, in neuroendocrine carcinomas of the stomach. (2014)
  • Author(s): Ishida M, Sekine S, Taniguchi H, Fukagawa T, Katai H, Kushima R.
  • Journal Title: Histopathology Volume: Jun;64(7) Pages: 1027-31
  • DOI: 10.1111/his.12348.
  • Peer Reviewed
• [Journal Article] Alternative mTOR signal activation in sorafenib-resistant hepatocellular carcinoma cells revealed by array-based pathway profiling. (2014)
  • Author(s): Masuda M, Chen WY, Miyanaga A, Nakamura Y, Kawasaki K, Sakuma T, Ono M, Chen CL, Honda K, Yamada T.
  • Journal Title: Mol Cell Proteomics. Volume: In press Pages: In press
  • Peer Reviewed
• [Journal Article] MicroRNA expression and functional profiles of osteosarcoma. (2014)
  • Author(s): Kobayashi E, Satow R, Ono M, Masuda M, Honda K, Sakuma T, Kawai A, Morioka H, Toyama Y, Yamada T.
  • Journal Title: Oncology Volume: 86(2): Pages: 94-103
  • DOI: doi: 10.1159/000357408
  • Peer Reviewed
• [Journal Article] 1) Adenocarcinoma arising from an anal gland-Report of a case. (2014)
  • Author(s): Sakamoto T, Konishi F, Yoshida T, Yoshinaga Y, Izumo T, Lefor A.
  • Journal Title: Int J Surg Case Rep. Volume: Mar 12;5(5): Pages: 234-236.
  • DOI: 10.1016/j.ijscr.2014.02.010.
  • Peer Reviewed
• [Journal Article] Immunohistochemical actinin-4 expression in infiltrating gliomas: association with WHO grade and differentiation. (2014)
  • Author(s): Fukushima S, Yoshida A, Honda K, Maeshima AM, Narita Y, Yamada T, Shibui S, Tsuda H.
  • Journal Title: Brain Tumor Pathol. Volume: Jan;31(1): Pages: 11-6.
  • DOI: . doi: 10.1007/s10014-013-0139-z. Epub 2013 Mar 17.
  • Peer Reviewed
• [Journal Article] Utility of PAX8 mouse monoclonal antibody in the diagnosis of thyroid, thymic, pleural, and lung tumors: a comparison with polyclonal PAX8 antibody. (2014)
  • Author(s): Toriyama A, Mori T, Sekine S, Yoshida A, Hino O, Tsuta K.
  • Journal Title: Histopathology Volume: On line Pages: On line
  • DOI: doi: 10.1111/his.12405.
  • Peer Reviewed
• [Journal Article] Secondary osteosarcoma developing 10 years after chemoradiotherapy for non-small-cell lung cancer. (2014)
  • Author(s): Yagishita S, Horinouchi H, Yorozu T, Kitazono S, Mizugaki H, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Mori T, Tsuta K, Sumi M, Tamura T.
  • Journal Title: Jpn J Clin Oncol Volume: Feb;44(2): Pages: 191-4.
  • DOI: 10.1093/jjco/hyt192.
  • Peer Reviewed
• [Journal Article] Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome. (2014)
  • Author(s): Arai E, Sakamoto H, Ichikawa H, Totsuka H, Chiku S, Gotoh M, Mori T, Nakatani T, Ohnami S, Nakagawa T, Fujimoto H, Wang L, Aburatani H, Yoshida T, Kanai Y.
  • Journal Title: Int J Cancer. Volume: On line Pages: On line
  • DOI: 10.1002/cam4.214.
  • Peer Reviewed
• [Journal Article] Basic study of soft tissue augmentation by adipose-inductive biomaterial (2014)
  • Author(s): Yazawa M, Mori T, Kishi K,
  • Journal Title: Journal of Biomedical Materials Research: Part B - Applied Biomaterials Volume: In press Pages: In press
  • Peer Reviewed
• [Journal Article] Twenty-six Cases of Advanced Ampullary Adenocarcinoma (2014)
  • Author(s): Shoji H, Morizane C, Hiraoka N, Kondo S, Ueno H, Ohno I, Shimizu S, Mitsunaga
  • Journal Title: Jpn J Clin Oncol. Volume: In press Pages: In press
  • Peer Reviewed
• [Journal Article] Intraductal dissemination of papillary adenocarcinoma of the (2014)
  • Author(s): Matsubara A, Nara S, Sekine S, Ojima H, Kosuge T, Shimada K, Kushima R, Kanai
  • Journal Title: Pathol Int. Volume: Jan;64(1): Pages: 39-44.
  • DOI: 10.1111/pin.12131.
  • Peer Reviewed
• [Journal Article] Histopathological characteristics of hypervascular cholangiocellular carcinoma as an early stage of cholangiocellular carcinoma. (2014)
  • Author(s): Sato Y, Ojima H, Onaya H, Mori T, Hiraoka N, Kishi Y, Nara S, Esaki M, Shimada
  • Journal Title: Hepatol Res. Volume: Sept 6 Pages: On line
  • DOI: 10.1111/hepr.12236.
  • Peer Reviewed
• [Journal Article] Lobular endocervical glandular hyperplasia is a neoplastic entity with frequent activating GNAS mutations. (2014)
  • Author(s): atsubara A, Sekine S, Ogawa R, Yoshida M, Kasamatsu T, Tsuda H, Kanai Y.
  • Journal Title: Am J Surg Pathol. Volume: 38(3) Pages: :370-6
  • DOI: 10.1097/PAS.0000000000000093.
  • Peer Reviewed
• [Journal Article] Frequent lack of GNAS mutations in colorectal adenocarcinoma associated with GNAS-mutated villous adenoma. (2014)
  • Author(s): Sekine S, Ogawa R, Oshiro T, Kanemitsu Y, Taniguchi H, Kushima R, Kanai Y.
  • Journal Title: Genes Chromosomes Cancer. Volume: 53(4): Pages: :366-72
  • DOI: 1002/gcc.2214
  • Peer Reviewed
• [Journal Article] Junctional Rab13-binding protein (JRAB) regulates cell spreading via filamins. (2013)
  • Author(s): Sakane A, Alamir Mahmoud Abdallah A, Nakano K, Honda K, Kitamura T, Imoto I, Matsushita N, Sasaki T
  • Journal Title: Genes Cells Volume: Sep;18(9): Pages: 1045-51.
  • DOI: doi: 10.1111/gtc.12078. Epub 2013 Jul 25.
  • Peer Reviewed
• [Journal Article] Soluble interleukin-6 receptor is a serum biomarker for the response of esophageal carcinoma to neoadjuvant chemoradiotherapy. (2013)
  • Author(s): Makuuchi Y, Honda K, Osaka Y, Kato K, Kojima T, Daiko H, Igaki H, Ito Y, Hoshino S, Tachibana S, Watanabe T, Furuta K, Sekine S, Umaki T, Watabe Y, Miura N, Ono M, Tsuchida A, Yamada T.
  • Journal Title: Cancer Sci. Volume: Aug;104(8): Pages: 1045-51.
  • DOI: doi: 10.1111/cas.12187. Epub 2013 Jun 13.
  • Peer Reviewed
• [Journal Article] SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis. (2013)
  • Author(s): Ohtomo R, Mori T, Shibata S, Tsuta K, Maeshima AM, Akazawa C, Watabe Y, Honda K, Yamada T, Yoshimoto S, Asai M, Okano H, Kanai Y, Tsuda H.
  • Journal Title: Mod Pathol. Volume: Aug;26(8): Pages: 1041-50.
  • DOI: doi: 10.1038/modpathol.2013.54. Epub 2013 Apr 5.
  • Peer Reviewed
• [Journal Article] 3) Three-dimensional reconstruction of oral tongue squamous cell carcinoma at invasion front. (2013)
  • Author(s): Kudo T, Shimazu Y, Yagishita H, Izumo T, Soeno Y, Sato K, Taya Y, Aoba T.
  • Journal Title: Int J Dent. Volume: On line Pages: On line
  • DOI: 10.1155/2013/482765.
  • Peer Reviewed
• [Journal Article] Peripheral odontogenic keratocyst associated with nevoid basal cell carcinoma syndrome: a case report. (2013)
  • Author(s): Sakamoto K, Morita KI, Shimada Y, Omura K, Izumo T, Yamaguchi A
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol. Volume: 2013 Dec 10. Pages: 523-3
  • DOI: 10.1016/j.oooo.2013.09.015.
  • Peer Reviewed
• [Journal Article] Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis. (2013)
  • Author(s): Yamazaki H, Mori T, Yazawa M, Maeshima AM, Matsumoto F, Yoshimoto S, Ota Y, Kaneko A, Tsuda H, Kanai Y.
  • Journal Title: Lab Invest. Volume: Dec;93(12): Pages: 1331-8
  • DOI: 10.1038/labinvest.2013.120.
• [Journal Article] Distinct outcome of stage I lung adenocarcinoma with ACTN4 cell motility gene amplification. (2013)
  • Author(s): Noro R1, Honda K, Tsuta K, Ishii G, Maeshima AM, Miura N, Furuta K, Shibata T, Tsuda H, Ochiai A, Sakuma T, Nishijima N, Gemma A, Asamura H, Nagai K, Yamada T.
  • Journal Title: Ann Oncol Volume: Oct;24(10): Pages: 2594-600
  • DOI: doi: 10.1093/annonc/mdt293. Epub 2013 Jul 30.
  • Peer Reviewed
• [Journal Article] Bile duct carcinoma involving the common channel associated with pancreaticobiliary maljunction shows an extension pattern similar to ductal carcinoma of the pancreas. (2013)
  • Author(s): Yoshida N, Esaki M, Kishi Y, Shimada K, Ojima H, Kanai Y, Hiraoka N.
  • Journal Title: Pathol Int Volume: Aug;63(8): Pages: 415-8.
  • DOI: 10.1111/pin.12085.
  • Peer Reviewed
• [Journal Article] Gemcitabine in patients with intraductal papillary mucinous neoplasm with an associated invasive carcinoma of the pancreas. (2013)
  • Author(s): Otsuka T, Morizane C, Nara S, Ueno H, Kondo S, Shimada K, Kosuge T, Ikeda M, Hiraoka N, Okusaka T
  • Journal Title: Pancreas. Volume: Jul;42(5) Pages: On line
  • DOI: 10.1097/MPA.0b013e3182826f1f.
  • Peer Reviewed
• [Journal Article] Early venous return in hepatic angiomyolipoma due to an intratumoral structure resembling an arteriovenous fistula. (2013)
  • Author(s): Iwao Y, Ojima H, Onaya H, Sakamoto Y, Kishi Y, Nara S, Esaki M, Mizuguchi Y, Ushigome M, Asahina D, Hiraoka N, Shimada K, Kosuge T, Kanai Y.
  • Journal Title: Hepatol Res. Volume: May 17 Pages: Online
  • DOI: 10.1111/hepr.12163.
  • Peer Reviewed
• [Journal Article] Pancreatic intraglandular metastasis predicts poorer outcome in postoperative patients with pancreatic ductal carcinoma. (2013)
  • Author(s): Oguro S, Shimada K, Ino Y, Esaki M, Nara S, Kishi Y, Kosuge T, Kanai Y, Hiraoka N.
  • Journal Title: Am J Surg Pathol. Volume: Jul;37(7): Pages: 1030-8.
  • DOI: 10.1097/PAS.0b013e3182834d22.
  • Peer Reviewed
• [Journal Article] High levels of FOXP3⁺ regulatory T cells in gastric MALT lymphoma predict responsiveness to Helicobacter pylori eradication. (2013)
  • Author(s): Iwaya Y, Kobayashi M, Momose M, Hiraoka N, Sakai Y, Akamatsu T, Tanaka E, Ohtani H, Fukuda M, Nakayama J.
  • Journal Title: Helicobacter. Volume: Oct;18(5) Pages: 356-62.
  • DOI: 10.1111/hel.12051.
  • Peer Reviewed
• [Journal Article] Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. (2013)
  • Author(s): : Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N.
  • Journal Title: Br J Cancer. Volume: Mar 5;108(4) Pages: 914-23.
  • DOI: 10.1038/bjc.2013.32.
  • Peer Reviewed
• [Journal Article] Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms. (2013)
  • Author(s): Nishikawa G, Sekine S, Ogawa R, Matsubara A, Mori T, Taniguchi H, Kushima R, Hiraoka N, Tsuta K, Tsuda H, Kanai Y.
  • Journal Title: Br J Cancer. Volume: Mar 5;108(4): Pages: 951-8
  • DOI: 10.1038/bjc.2013.47.
  • Peer Reviewed
• [Journal Article] Risk factors for lymphatic and venous involvement in endoscopically resected gastric cancer. (2013)
  • Author(s): Sekiguchi M, Sekine S, Oda I, Nonaka S, Suzuki H, Yoshinaga S, Taniguchi H, Tsuda H, Kushima R, Saito Y.
  • Journal Title: J Gastroenterol. Volume: 48(6) Pages: 706-12
  • DOI: 10.1007/s00535-012-0696-7.
  • Peer Reviewed
• [Journal Article] Dome-type carcinoma of the colon masquerading a submucosal tumor. (2013)
  • Author(s): Yamada M, Sekine S, Matsuda T.
  • Journal Title: Clin Gastroenterol Hepatol. Volume: 11(10):A30. Pages: On line
  • DOI: 10.1097/PAS.0b013e31828ff59d.
  • Peer Reviewed
• [Journal Article] Gastric adenocarcinoma of the fundic gland type shares common genetic and phenotypic features with pyloric gland adenoma. (2013)
  • Author(s): Kushima R, Sekine S, Matsubara A, Taniguchi H, Ikegami M, Tsuda H.
  • Journal Title: Pathol Int Volume: ;63(6) Pages: 318-25
  • DOI: 10.1111/pin.12070.
  • Peer Reviewed
• [Presentation] Actinin-4 expression is a predictive biomarker for late metastasis of cervical lymph nodes in early-stage tongue cancer (2014)
  • Author(s): Kazufumi Honda1, Yukio Watabe1,2, Takeshi Nomura2, Takahiko Shibahara2, and Tesshi Yamada1
  • Organizer: Taiwan Maxillofacial Oral Surgery
  • Place of Presentation: Tainan Taiwan
  • Year and Date: 20140308-20140308
• [Presentation] Rapid biomarker validation by high-density plasma protein array (2013)
  • Author(s): Honda K, Yamada T
  • Organizer: 3rd Reverse-Phase Protein Array (RPPA) Global Workshop
  • Place of Presentation: Kobe Japan
  • Year and Date: 20131112-20131112
  • Invited
• [Presentation] Screening of novel molecular targets for tongue cancer using antibody-based proteomics (2013)
  • Author(s): Yukio Watabe1,2, Kazufumi Honda*1, Taisuke Mori3, Takafumi Watanabe1, Takeshi Nomura2, Takahiko Shibahara2, and Tesshi Yamada1
  • Organizer: International Conference Oral and Maxillofacial Surgery
  • Place of Presentation: Barcelona Spein
  • Year and Date: 20131021-20131024
• [Presentation] がん個別化医療選択のためのバイオマーカー開発と実用化
  • Author(s): 本田一文
  • Organizer: 国際癌治療増感研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 個別化医療バイオマーカーの同定と実用化
  • Author(s): 本田一文
  • Organizer: 日本口腔外科学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] The mechanism of resistance for chemotherapy in advanced stage of ovarian cancer
  • Author(s): Kazufumi Honda1, Sohei Yamamoto2, Hitoshi Tsuda2,3, Nami Miura1, Mitsuyo Omura4, Yoshihiro Izumi5, Masashi Takano6, Takahiro Kasamatsu7, Masaru Yoshida5, Makoto Suematsu4 & Tesshi Yamada1
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] シスタチオニンγリアーゼ（CSE)の阻害は、シスプラチンの効果を増強する
  • Author(s): 本田一文
  • Organizer: がんと代謝研究会
  • Place of Presentation: 鶴岡市
  • Invited
• [Presentation] 難治がん早期診断血液バイオマーカーの開発と多施設共同研究による迅速検証法の構築
  • Author(s): 本田一文、山田哲司
  • Organizer: 日本臨床検査医学会総会
  • Place of Presentation: 神戸市
  • Invited