Significance of reduced alphaGlcNAc glycosylation in pyloric gland neoplasms

• Project/Area Number: 19K16555
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Keio University
• Principal Investigator: Yamanoi Kazuhiro 慶應義塾大学, 医学部(信濃町), 講師 (80464965)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 幽門腺型 / MUC6 / 糖鎖修飾 / 多段階発がん / 前がん / 腫瘍マーカー / 胃型形質 / 粘液 / αlcNAc / 幽門腺 / 糖鎖 / 胃型粘液 / αGlcNAc / 肺癌 / 腺癌 / filopodia / FSCN / aGlcNAc / 幽門腺型粘液 / 胆道癌 / BilIN / 胃底腺型胃癌 / 分化 / alphaGlcNAc / 多段階発癌

Outline of Research at the Start

本研究では、胃、膵臓、子宮頸部のがん病変、前がん病変におけるαGlcNAcの発現低下について、予後を含めた悪性度の関係まで調べ、対象臓器も肺、胆道などに広げて検討することを１つの目的とする。がん由来の培養細胞株を用いて、αGlcNAcの発現に呼応する細胞機能の変化と、関連する遺伝子発現やリン酸化の変化を調べ、αGlcNAcががんの悪性化を抑制する分子生物学的な機序を明らかにし、αGlcNAcの発現変化を基盤とした、新たな治療標的の知見を得ることが２つ目の目的である。
本研究で、がんの悪性化に関わる糖鎖修飾の変化が臓器横断的に理解されれば、糖鎖修飾を鍵にした新たながんの治療標的の研究の基盤になる。

Outline of Final Research Achievements

Gstric gland mucin consists core protein MUC6 with
α1,4-N-acetylglucosamine (αGlcNAc) glycosylation. Mice deficient
in αGlcNAc develop gastric adenocarcinoma. In human, αGlcNAc glycosylation was frequently lost in adenocarcinoma expressing gastric mucin. We have studied MUC6 and αGlcNAc expression in malignant and pre-malignant lesions with gastric mucin expression in extra-gastric organs. In all organs, decreased αGlcNAc-glycosylation on MUC6 was frequently observed in not only malignant but pre-malignant lesions. Furthermore, in uterine cervix, patients with αGlcNAc negative adenocarcinoma had poor prognosis. In lung, those with MUC6 negative adenocarcinoma had poor prognosis. Furthermore we studied MUC6 and αGlcNAc effect in cancer cell line models. Ectopic MUC6 expression attenuated cancer malignancy, and αGlcNAc glycosylation enhanced its phenotypes. These results show that phenotypic change of mucin is a malignant biomarker in various organ neoplasms with gastric mucin.

Academic Significance and Societal Importance of the Research Achievements

幽門腺型粘液の産生を伴う腫瘍は、諸臓器においてみられるが、しばしば、組織学的に、細胞異型に乏しい症例が存在する。ゆえに、病理診断の現場において、その早期病変の診断が難しい場合がある。本研究によって、早期病変マーカーとしてαGlcNAcの低下・消失が明らかになったことで、幽門腺型粘液の産生を伴う腫瘍の早期診断の大きな一助になると考えられる。また、ヒトがん由来培養細胞株を用いた実験により、MUC6の発現、αGlcNAcの糖鎖修飾低下が、直接、がん細胞の悪性化にかかわることが明らかになった。今後その機序をさらに明らかにすることで、これらの腫瘍に対する、新たな分子標的療法が可能になると考えられる。

Research Products

• [Journal Article] Glycosylation of MUC6 by α1,4-linked N-acetylglucosamine enhances suppression of pancreatic cancer malignancy (2022)
  • Author(s): Yuki A, Fujii C, Yamanoi K, Matoba H, Harumiya S, Kawakubo M, Nakayama J
  • Journal Title: Cancer Science Volume: 113 Issue: 2 Pages: 576-586
  • DOI: 10.1111/cas.15209
  • Peer Reviewed / Open Access
• [Journal Article] MUC6 expression is a preferable prognostic marker for invasive mucinous adenocarcinoma of the lung (2022)
  • Author(s): Yamanoi K, Fujii C, Yuzuriha H, Kumazawa M, Shimoda M, Emoto K, Asamura H, Nakayama J
  • Journal Title: Histochemistry and Cell Biology Volume: Online ahead of print Issue: 6 Pages: 671-684
  • DOI: 10.1007/s00418-022-02093-1
  • Peer Reviewed
• [Journal Article] Decreased alpha‐1,4‐linked N‐acetylglucosamine glycosylation in biliary tract cancer progression from biliary intraepithelial neoplasia to invasive adenocarcinoma (2020)
  • Author(s): Okumura Motohiro、Yamanoi Kazuhiro、Uehara Takeshi、Nakayama Jun
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4629-4635
  • DOI: 10.1111/cas.14677
  • Peer Reviewed / Open Access
• [Journal Article] Diffuse MIST1 expression and decreased α1,4‐linked N‐acetylglucosamine (αGlcNAc) glycosylation on MUC6 are distinct hallmarks for gastric neoplasms showing oxyntic gland differentiation (2020)
  • Author(s): Yamada Shigenori、Yamanoi Kazuhiro、Sato Yoshiko、Nakayama Jun
  • Journal Title: Histopathology Volume: 77 Issue: 3 Pages: 413-422
  • DOI: 10.1111/his.14165
  • Peer Reviewed
• [Journal Article] Analysis of A4gnt Knockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda (2019)
  • Author(s): Masatomo Kawakubo, Hitomi Komura, Yukinobu Goso, Motohiro Okumura, Yoshiko Sato, Chifumi Fujii, Masaki Miyashita, Nobuhiko Arisaka, Satoru Harumiya, Kazuhiro Yamanoi, Shigenori Yamada, Shigeru Kakuta, Hiroto Kawashima, Michiko N Fukuda, Minoru Fukuda, Jun Nakayama
  • Journal Title: J Histochem Cytochem Volume: 67 Issue: 10 Pages: 759-770
  • DOI: 10.1369/0022155419860134
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] αGlcNAc and its catalyst α4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type (2019)
  • Author(s): Ida Koichi、Yamanoi Kazuhiro、Asaka Shiho、Takeuchi Hodaka、Miyamoto Tsutomu、Shiozawa Tanri、Nakayama Jun
  • Journal Title: Scientific Reports Volume: 9 Issue: 1
  • DOI: 10.1038/s41598-019-49376-7
  • Peer Reviewed / Open Access
• [Presentation] Phenotypic change of pyloric gland mucin represents potentially malignant biomarker for various neoplasms (2022)
  • Author(s): Kazuhiro Yamanoi, Chifumi Fujii, Masayuki Shimoda, Jun Nakayama
  • Organizer: The 81st Annual Meeting of the Japanese Cancer Association
• [Presentation] αGlcNAc binding to MUC6 enhances suppression of malignant phenotypes of pancreatic cancer cells (2022)
  • Author(s): Chifumi Fujii, Kazuhiro Yamanoi, Hisanori Matoba, Jun Nakayama
  • Organizer: The 81st Annual Meeting of the Japanese Cancer Association
• [Presentation] 胃底腺型胃癌は、αGlcNAc糖鎖修飾の不十分な未熟腺頸部粘液細胞の形質を主に有する腫瘍である (2021)
  • Author(s): 山ノ井 一裕, 山田 重徳, 中山 淳
  • Organizer: 第110回日本病理学会総会
• [Presentation] MUC6 expression is a novel preferable prognostic marker for invasive mucinous adenocarcinoma of the lung. (2021)
  • Author(s): Kazuhiro Yamanoi, Chifumi Fujii, Jun Nakayama, Masayuki Shimoda
  • Organizer: 第80回日本癌学会学術総会
  • Int'l Joint Research
• [Presentation] Phenotypic change of gastric gland mucin is a malignant potential biomarker for stomach, pancreas, bile duct and uterine cervix neoplasms. (2021)
  • Author(s): Kazuhiro Yamanoi
  • Organizer: Manchester Pathology 2021, 13th Joint meeting of the BDIAP and The Pathological Society
  • Int'l Joint Research
• [Presentation] Significance of aGlcNAc expression in biliary ductal cancer progression (2020)
  • Author(s): 山ノ井 一裕, 奥村 征大, 上原 剛, 尾島 英知, 中山 淳
  • Organizer: 第109回 日本病理学会総会
• [Presentation] 胃腺粘液産生子宮頸部腫瘍におけるαGlcNAcとα4GnTの発現意義 (2019)
  • Author(s): 山ノ井 一裕, 井田 耕一, 浅香 志穂, 竹内 穂高, 宮本 強, 塩沢 丹里, 中山 淳
  • Organizer: 第108回日本病理学会総会
• [Presentation] 子宮頸部細胞診で胃型粘液性癌が疑われた通常型内頸部腺癌の一例 (2019)
  • Author(s): 服部 守恭, 藤井 真一, 山ノ井 一裕, 中山 淳, 福島 万奈, 的場 久典
  • Organizer: 第58回日本臨床細胞学会秋期大会
• [Presentation] Significance of αGlcNAc expression during progression of cholangiocarcinoma (2019)
  • Author(s): Motohiro Okumura, Kazuhiro Yamanoi, Jun Nakayama
  • Organizer: The 78th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research