Establishment of early diagnosis system of pancreatobiliary carcinomas by the application of mucin expression profiles

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390085
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kagoshima University
• Principal Investigator: YONEZAWA Suguru 鹿児島大学, 医歯(薬)学総合研究科, 教授 (10175002)
• Co-Investigator(Kenkyū-buntansha): HIGASHI Michiyo 鹿児島大学, 医歯学総合研究科, 准教授 (60315405) ; YOKOYAMA Seiya 鹿児島大学, 医歯学総合研究科, 助教 (20569941) ; SHINCHI Hiroyuki 鹿児島大学, 医歯学総合研究科, 教授 (60284874) ; NARIMATSU Hisashi 独立行政法人産業技術総合研究所, 糖鎖医工学研究センター, センター長 (40129581) ; KAMEYAMA Akihiko 独立行政法人産業技術総合研究所, 糖鎖医工学研究センター, チーム長 (80415661)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 膵癌 / IPMN / mucin / DNA methylation / diagnosis / angiogenesis

Research Abstract

It is very difficult to perform an early detection of pancreatic ductal adenocarcinomas (PDACs) or an accurate differential diagnosis for subtypes of intraductal papillary mucinous neoplasms (IPMNs) with different outcome. Expression profiles of MUC1, MUC2 and MUC4 are different between PDACs and IPMNs. We developed a methylation-specific electrophoresis (MSE) method to analyze the DNA methylation status.
By using the MSE, we evaluated pancreatic juices from 45 patients. The predictive diagnosis by MSE showed sensitivity and specificity of 80% and 87% for PDAC; 88% and 100% for intestinal-type IPMN; and 77% and 88% for gastric-type IPMN; respectively. The MSE analysis of pancreatic juices may give us useful informations for diagnosis of human pancreatic neoplasms. Another study for the first time demonstrated a pivotal role of MUC1 in controlling the hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors in PDAC cells.

Research Products

• [Journal Article] Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice (2014)
  • Author(s): Yokoyama S, Kitamoto S, Higashi M, Goto Y, Hara T, Ikebe D, Yamaguchi T, Arisaka Y, Niihara, Nishimata H, Tanaka S, Takaori K, Batra S K, Yonezawa S
  • Journal Title: PLoS ONE Volume: 9(4) Pages: e93760
  • DOI: 10.1371/journal.pone.0093760
  • Peer Reviewed
• [Journal Article] Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer (2014)
  • Author(s): Shibahara H, Higashi M, Koriyama C, Yokoyama S, Kitazono I, Yasuhiro K, Narita M, Kuze S, Takanori K, Mita S, Arai T, Kato T, Yuasa N, Yamaguchi R, Kubota H, Suzuki H, Baba S, Rousseau K, Batra S K, Yonezawa S
  • Journal Title: PLoS ONE Volume: 9(4) Pages: e86111
  • DOI: 10.1371/journal.pone.0086111
  • Peer Reviewed
• [Journal Article] Expression of MUC4 mucin is observed mainly in the intestinal-type of intraductal papillary mucinous neoplasm of the pancreas (2013)
  • Author(s): Kitazono I, Higashi M, Kitamoto S, Yokoyama S, Horinouchi M, Osako M, Shimizu T, Tabata M, Batra S K, Goto M, Yonezawa S
  • Journal Title: Pancreas Volume: 42(7) Pages: 1120-1128
  • DOI: 10.1097/MPA.0b013e3182965915
  • Peer Reviewed
• [Journal Article] MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors (2013)
  • Author(s): Kitamoto S, Yokoyama S, Higashi M, Yamada N, Takao S, Yonezawa S
  • Journal Title: Oncogene Volume: 32(39) Pages: 4614-4621
  • DOI: 10.1038/onc.2012.478
  • Peer Reviewed
• [Journal Article] Identification of mucins by using a method involving a combination of on-membrane chemical deglycosylation and immunostaining (2013)
  • Author(s): Matsuno YK, Dong W, Yokoyama S, Yonezawa S, Narimatsu H, Kameyama A
  • Journal Title: Journal of Immunological Methods Volume: 394(1-2) Pages: 125-30
  • DOI: 10.1016/j.jim.2013.06.002
  • Peer Reviewed
• [Journal Article] MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis : an immunohistochemical study of early gastric cancer (2012)
  • Author(s): Tamura Y, Higashi M, Kitamoto S, Yokoyama S, Osako M, Horinouchi M, Shimizu T, Tabata M, Batra SK, Goto M, Yonezawa S
  • Journal Title: PLoS ONE Volume: 7(11) Pages: e49251
  • DOI: 10.1371/journal.pone.0049251
  • Peer Reviewed
• [Journal Article] Expression of MUC17 is regulated by HIF1 α -mediated hypoxic responses and requires a methylation-free hypoxia responsible element in pancreatic cancer (2012)
  • Author(s): Kitamoto S, Yokoyama S, Higashi M, Yamada N, Matsubara S, Takao S, Batra S K, Yonezawa S
  • Journal Title: PLoS ONE Volume: 7(9) Pages: e44108
  • DOI: 10.1371/journal.pone.0044108
  • Peer Reviewed
• [Journal Article] A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain : use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach (2012)
  • Author(s): Yonezawa S, Kitajima S, Higashi M, Osako M, Horinouchi M, Yokoyama S, Kitamoto S, Yamada N, Tamura Y, Shimizu T, Tabata M, Goto M
  • Journal Title: Gastric Cancer Volume: 15(4) Pages: 370-381
  • DOI: 10.1007/s10120-011-0125-2
  • Peer Reviewed
• [Journal Article] The application of methylation specific electrophoresis (MSE) to DNA methylation analysis of the 5' CpG island of mucin in cancer cells (2012)
  • Author(s): Yokoyama S, Kitamoto S, Yamada N, Houjyo I, Sugai T, Nakamura S, Arisaka Y, Takaori K, Higashi M, Yonezawa S
  • Journal Title: BMC Cancer Volume: 12 Pages: 67
  • DOI: 10.1186/1471-2407-12-67
  • Peer Reviewed
• [Journal Article] Pathobiological implications of expression of MUC16/CA125 in intrahepatic cholangiocarcinoma-mass forming type (2012)
  • Author(s): Higashi M, Yamada N, Yokoyama S, Kitamoto S, Tabata K, Koriyama C, Batra SK, Yonezawa S
  • Journal Title: Pathobiology Volume: 79(2) Pages: 101-106
  • DOI: 10.1159/000335164
  • Peer Reviewed
• [Journal Article] Improved method for immunostaining of mucin separated by supported molecular matrix electrophoresis by optimizing the matrix composition and fixation procedure (2011)
  • Author(s): Matsuno Y, Dong W, Yokoyama S, Yonezawa S, Saito T, Gotoh M, Narimatsu H, Kameyama A
  • Journal Title: Electrophoresis Volume: 32(14) Pages: 1829-1836
  • DOI: 10.1002/elps.201000608
  • Peer Reviewed
• [Journal Article] Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas (2011)
  • Author(s): Furukawa T, Hatori T, Fujita I, Yamamoto M, Kobayashi M, Ohike N, Morohoshi T, Egawa S, Unno M, Takao S, Osako M, Yonezawa S, Mino-Kenudson M, Lauwers GY, Yamaguchi H, Ban S, Shimizu M
  • Journal Title: Gut Volume: 60(4) Pages: 509-516
  • DOI: 10.1136/gut.2010.210567
  • Peer Reviewed
• [Journal Article] Mucins in human neoplasms : Clinical pathology, gene expression and diagnostic application (2011)
  • Author(s): Yonezawa S, Higashi M, Yamada N, Yokoyama S, Kitamoto S, Kitajima S, Goto M
  • Journal Title: Pathology International Volume: 61(12) Pages: 697-716
  • DOI: 10.1111/j.1440-1827.2011.02734.x
  • Peer Reviewed
• [Journal Article] Epigenetic regulation of mucin genes in human cancers (2011)
  • Author(s): Yamada N, Kitamoto S, Yokoyama S, Hamada T, Goto M, Tsutsumida H, Higashi M, Yonezawa S
  • Journal Title: Clinical Epigenetics Volume: 2(2) Pages: 85-96
  • DOI: 10.1007/s13148-011-0037-3
  • Peer Reviewed
• [Presentation] Application of a novel DNA methylation analysis method (MSE) for mucin expression in pancreatic, biliary and pulmonary neoplasms, MUCINS IN HEALTH AND DISEASE (2013)
  • Author(s): Yonezawa S, Yokoyama S, Kitamoto S, Higashi M
  • Organizer: 12th International Workshop on Carcinoma-associated Mucins
  • Place of Presentation: Robinson College (Cambridge, UK)
  • Year and Date: 20130727-31
• [Presentation] Examination of mucin expression including a novel DNA methylation analysis method (MSE) : Its application for diagnosis of human pancreatic neoplasms (2012)
  • Author(s): Yonezawa S
  • Organizer: International Symposium on Pancreas Cancer 2012
  • Place of Presentation: 京都国際コンベンションセンター(京都)
  • Year and Date: 20121004-06
  • Invited
• [Presentation] Epigenetic status analysis of mucin expression including a novel DNA Methylation analysis method (MSE) : Its application for early diagnosis of human pancreatic neoplasms, MUCINS IN HEALTH AND DISEASE (2011)
  • Author(s): Yonezawa S
  • Organizer: 11th International Workshop on Carcinoma-associated Mucins
  • Place of Presentation: Robinson College (Cambridge, UK)
  • Year and Date: 20110709-13
  • Invited
• [Book] 膵腫瘍におけるムチンコア蛋白(MUC)の分子病理 (分担執筆), 専門医のための消化器病学第2版. (小俣政男, 千葉勉;監修, 下瀬川徹, 渡辺守, 木下芳一, 金子周一, 樫田博史;編集) (2013)
  • Author(s): 米澤 傑, 東美智代
  • Total Pages: 686(642-645)
  • Publisher: 医学書院, 東京
• [Book] 病理診断に役立つ分子生物学(病理と臨床臨時増刊号 Vol.29) (分担執筆), 第 2 部 病理診断医になじみのある疾患関連分子, MUC 解説編. (金井弥栄, 石川俊平, 池田栄二;編集) (2011)
  • Author(s): 米澤 傑, 山田宗茂, 横山勢也, 北本 祥, 田畑和宏, 東美智代
  • Total Pages: 545(328-333)
  • Publisher: 株式会社文光堂
• [Book] 病理診断に役立つ分子生物学(病理と臨床臨時増刊号 Vol.29) (分担執筆), 第 2 部 病理診断医になじみのある疾患関連分子, MUC 診断編. (金井弥栄, 石川俊平, 池田栄二;編集) (2011)
  • Author(s): 米澤 傑, 山田宗茂, 横山勢也, 北本 祥, 田畑和宏, 東美智代
  • Total Pages: 545(334-340)
  • Publisher: 株式会社文光堂, 東京
• [Remarks] 鹿児島大学医歯学総合絵研究科先進治療科学専攻腫瘍学講座人体がん病理学
  • URL: http://www.kufm.kagoshima-u.ac.jp/~byouri2/
• [Remarks] 難治性の膵がんを糖タンパク質「ムチン」の高感度分析法で早期診断する(日本病理学会ホームページ)
  • URL: http://pathology.or.jp/ippan/pdf/yonezayo.pdf
• [Patent(Industrial Property Rights)] ムチン(MUC1)タンパク質に対する抗体及びその用途 (2013)
  • Inventor(s): 米澤 傑
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 13/577, 841
  • Filing Date: 2013-04-23
  • Overseas
• [Patent(Industrial Property Rights)] METHOD FOR DIAGNOSING TYPE OF PANCREATIC TUMOR (2012)
  • Inventor(s): 横山勢也, 米澤 傑, 北本 祥
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012JP067262
  • Filing Date: 2012-06-29
  • Overseas
• [Patent(Industrial Property Rights)] NOVEL DNA METHYLATION ANALYSIS METHOD (2011)
  • Inventor(s): 横山勢也, 米澤 傑
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2011JP060339
  • Filing Date: 2011-04-21
  • Overseas