Molecular pathways and functional varieties of hemophagocytosis-induced keratinization in oral squamous cell carcinoma cells: from cell death to proliferation and invasion

• Project/Area Number: 15K15693
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Osaka Dental University (2016); Niigata University (2015)
• Principal Investigator: SAKU Takashi 大阪歯科大学, 歯学部, 客員教授 (40145264)
• Co-Investigator(Kenkyū-buntansha): 程 クン 新潟大学, 医歯学系, 准教授 (40207460) ; 丸山 智 新潟大学, 医歯学総合病院, 講師 (30397161) ; 山崎 学 新潟大学, 医歯学系, 助教 (10547516) ; 阿部 達也 新潟大学, 医歯学総合病院, 医員 (70634856) ; 田中 昭男 大阪歯科大学, 歯学部, 教授 (10121823)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 病理学 / 実験腫瘍学 / 口腔扁平上皮癌 / ヘモグロビン誘導 / 角化機序

Outline of Final Research Achievements

We have defined the keratinization of oral squamous cell carcinoma as skin-type orthokeratinization due to keratin 17 expression which never occurs in normal oral mucosa. Such an expression of dyskeratotic keratin 17 was shown to be induced by hemophagacytosis-derived hemoglobin released from erythrocytes and to mediate expressions of OH-1, PAR-2, 14-3-3σ, and YAP. These functional factors contributed to molecular pathways not only for cell death but for cellular proliferation and invasion in oral squamous cell carcinoma. In addition, cell death in oral lichen planus was explained by similar mechanisms starting from hemophagacytosis because hemorrhage often occurred along the epithelial interface, and keratinization-based cellular evaluation was confirmed to be useful in oral cytology to diagnose malignancy. This much functional varieties of phagocytosis-mediated keratinization were never expected, when we formulated our hypothesis that keratinization is initiated by hemophagocytosis.

Research Products

• [Journal Article] A retrospective multi-institutional study on the clinical categorization and diagnosis of oral lichen plants (2017)
  • Author(s): Ito D, Sugawara Y, Jinbu Y, Nakamura S, Fujibayashi T, Maeda H, Hasegawa H, Saku T, Tanaka A, Komiyama K
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: in press Issue: 5 Pages: 452-457
  • DOI: 10.1016/j.ajoms.2017.03.010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Differential diagnosis of well-differentiated squamous cell carcinoma from non-neoplastic oral mucosal lesions: New cytopathologic evaluation method dependent on keratinization-related parameters but not nuclear atypism (2017)
  • Author(s): Hara H, Misawa T, Ishii E, Nakagawa M, Koshiishi S, Amamiya K, Oyama T, Tominaga K, Cheng J, TanakaA, Saku T
  • Journal Title: Diagnostic Cytopathology Volume: 45 Issue: 5 Pages: 406-417
  • DOI: 10.1002/dc.23685
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proteomic and histopathological characterization of the interface between oral squamous cell carcinoma invasion fronts and non-cancerous epithelia (2017)
  • Author(s): Abe T, Maruyama S, Yamazaki M, Xu B, Babkair H, Sumita Y, Cheng J, Yamamoto T, Saku T
  • Journal Title: Experimental and Molecular Pathology Volume: 102 Issue: 2 Pages: 327-336
  • DOI: 10.1016/j.yexmp.2017.02.018
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aberrant expression of the tight junction molecules claudin-1 and zonula occludens-1 mediates cell growth and invasion in oral squamous cell carcinoma (2016)
  • Author(s): Babkair H, Yamazaki M, Uddin MS, Maruyama S, Abe T, Essa A, Sumita Y, Ahsan MS, Swelam W, Cheng J, Saku T
  • Journal Title: Human Pathology Volume: 57 Pages: 51-60
  • DOI: 10.1016/j.humpath.2016.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Basaloid squamous cell carcinoma of the uvula: report of a case and review of the literature (2016)
  • Author(s): Hara Y, Ikeda N, Takagi R, Horino K, Iida A, Nishiyama H, Hayashi T, Cheng J, Saku T
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 28 Issue: 3 Pages: 234-238
  • DOI: 10.1016/j.ajoms.2015.10.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa. (2016)
  • Author(s): Hasegawa M, Cheng J, Maruyama S, Yamazaki M, Abe T, Babkair H, Saito C, Saku T.
  • Journal Title: Pathol Res Pract. Volume: 212(5) Issue: 5 Pages: 426-436
  • DOI: 10.1016/j.prp.2016.02.016
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-associated macrophages are recruited and differentiated in the neoplastic stroma of oral squamous cell carcinoma. (2016)
  • Author(s): Essa AAM, Yamazaki M, Maruyama S, Abe T, Babkair H, Raghib AM, Megahed EMED, Cheng J, Saku T.
  • Journal Title: Pathologｙ Volume: 48（3） Issue: 3 Pages: 219-227
  • DOI: 10.1016/j.pathol.2016.02.006
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Geriatric oral lesions: A multicentric study (2016)
  • Author(s): Dhanuthai K, Rojanawatsirivej S, Somkotra T, Shin HI, Hong SP, Darling M, Ledderhof N, Khalili M, Thosaporn W, Rattana-Arpha P, Saku T
  • Journal Title: Geriatrics & Gerontology International Volume: 16 Issue: 2 Pages: 237-243
  • DOI: 10.1111/ggi.12458
  • Peer Reviewed / Open Access
• [Journal Article] Protease-activated receptor-2 modulates proliferation and invasion of oral squamous cell carcinoma cells. (2015)
  • Author(s): Al-Eryani K, Cheng J, Abe T, Maruyama S, Yamazaki M, Babkair H, Essa A, Saku T
  • Journal Title: Human Pathology Volume: in press Issue: 7 Pages: 991-999
  • DOI: 10.1016/j.humpath.2015.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Keratin 17 is co-expressed with 14-3-3 sigma in oral carcinoma in situ and squamous cell carcinoma and modulates cell proliferation and size but not cell migration. (2015)
  • Author(s): Mikami T, Maruyama S, Abe T, Kobayashi T, Yamazaki M, Funayama A, Shingaki S, Kobayashi T, Jun C, Saku T.
  • Journal Title: Virchows Arch. Volume: 466(5) Issue: 5 Pages: 559-69
  • DOI: 10.1007/s00428-015-1735-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 白板症型の口腔がんの増加 ー 悪性境界病変の病理診断の重要性 ー (2017)
  • Author(s): 朔 敬
  • Organizer: 鹿児島市歯科医師会平成28年度後期学会
  • Place of Presentation: 鹿児島市歯科医師会館，鹿児島市
• [Presentation] Tumor-associated macrophages are recruited and differentiated in the neoplastic stroma of oral squamous cell carcinoma (2016)
  • Author(s): Essa AAM, Yamazaki M, SMaruyama S, Abe; T, Babkair H, Raghib AM, Megahed EMED, Cheng J, Saku T
  • Organizer: Cell Symposia 100 Years of Phagocytes
  • Place of Presentation: Giardini Naxos, Sicily, Italy
  • Year and Date: 2016-09-19
  • Int'l Joint Research
• [Presentation] Oral squamous cell papillomas arise in the dual opening of mucous glands (2016)
  • Author(s): Saku T, Maruyama S, Yamasaki M, Abe T, Babkair H, Sumita Y, Cheng J
  • Organizer: 23rd Congress of the European Association for Cranio-maxillo-facial Surgery
  • Place of Presentation: The Queen Elizabeth II Conference Centre, London, UK
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] Histopathogenetic varieties of mucous gland ductal openings in the oral mucosa (2016)
  • Author(s): Saku T
  • Organizer: 39th Annual Congress of the Association for Dental Sciences of the Republic of China
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2016-09-02
  • Int'l Joint Research
• [Presentation] Proteome profiling at the lateral interface of oral squamous cell carcinoma/carcinoma in-situ (2016)
  • Author(s): Abe T, Maruyama S, Yamazaki M, Babkair H, Sumita Y, Cheng J, Saku T
  • Organizer: 第27回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 広島大学広仁会館，広島市
  • Year and Date: 2016-08-10
• [Presentation] 口腔粘膜乳頭種は粘液腺導管開口部に発生する (2016)
  • Author(s): 朔 敬，丸山 智，山﨑 学，阿部 達也，バブカイール ハムザ，隅田 賢正，程 クン
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター会議棟・展示棟，仙台市
  • Year and Date: 2016-05-12
• [Presentation] 口腔表在癌と非癌部粘膜上皮との界面における細胞競合現象の解析 (2016)
  • Author(s): 阿部 達也，丸山 智，山﨑 学，許 波，Hamzah Babkair， 隅田 賢正，程 クン， 山本 格，朔 敬
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター会議棟・展示棟，仙台市
  • Year and Date: 2016-05-12
• [Presentation] Proteomics of the lateral interface of oral squamous cell carcinoma (2016)
  • Author(s): Abe T, Maruyama S, Yamazaki M, Cheng J, Saku T
  • Organizer: The Global Oral Cancer Forum
  • Place of Presentation: New York University's Kimmel Center, New York, USA
  • Year and Date: 2016-03-04
  • Int'l Joint Research
• [Presentation] 口腔表在性癌と非癌部粘膜上皮との界面における細胞競合現象 (2015)
  • Author(s): 阿部達也, 丸山 智, 山崎 学, Babkair H, 隅田賢正, 程 クン, 朔 敬
  • Organizer: 平成27年度新潟歯学会第２回例会
  • Place of Presentation: 新潟大学歯学部講堂, 新潟市
  • Year and Date: 2015-11-07
• [Presentation] YAP modulates proliferation-differentiation phase switching in oral squamous cell carcinoma and its differentiation represents skin-type orthokeratosis (2015)
  • Author(s): Abe T, Maruyama S, Yamazaki M, Babkair H, Sumita Y, Cheng J, Saku T
  • Organizer: 7th Annual Meeting of Asia Society of Oral & Maxillofacial Pathology
  • Place of Presentation: Howard International House, Taipei, Taiwan
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Histopathological diagnostic criteria of oral carcinoma in-situ: The first and key step for better treatment of oral cancer to be shared equally across the world (2015)
  • Author(s): Saku T
  • Organizer: 7th Annual Meeting of Asia Society of Oral & Maxillofacial Pathology
  • Place of Presentation: Howard International House, Taipei, Taiwan
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] YAPは口腔扁平上皮癌の増殖―分化の分岐スイッチの役目を担っている：正角化関連分子の動態解析から (2015)
  • Author(s): 阿部達也, 丸山 智, 山崎 学, Babkair H, 隅田賢正, 程 クン, 朔 敬
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館, 札幌市
  • Year and Date: 2015-07-29
• [Presentation] GAS6/MERTK axis in oral squamous cell carcinoma: a possible mechanism for apoptotic cancer cell clearance by cancer cells and macrophages (2015)
  • Author(s): 山崎 学, 丸山 智, 阿部達也, 程 クン, 朔 敬
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館, 札幌市
  • Year and Date: 2015-07-29
• [Presentation] Tight junction molecules are differentially engaged in the neoplastic process of oral squamous epithelial cells towards squamous cell carcinoma (2015)
  • Author(s): Babkair H, Yamazaki M, Abe; T, Maruyama S, Sumita Y, Cheng J, Saku T
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館, 札幌市
  • Year and Date: 2015-07-29
• [Presentation] 口腔扁平上皮癌における皮膚型角化の分化誘導と細胞増殖の調整機構 (2015)
  • Author(s): 阿部達也, 丸山 智, 山崎 学, Babkair H, 隅田賢正, 程 クン, 朔 敬
  • Organizer: 平成27年度新潟歯学会第１回例会
  • Place of Presentation: 新潟大学歯学部講堂, 新潟市
  • Year and Date: 2015-07-11
• [Presentation] Tight junction molecules are differentially involved in malignant transformation steps of oral squamous epithelial cells towards squamous cell carcinoma (2015)
  • Author(s): Babkair H, Yamazaki M, Abe T, Maruyama S, Sumita Y, Cheng J, Saku T
  • Organizer: 平成27年度新潟歯学会第１回例会
  • Place of Presentation: 新潟大学歯学部講堂, 新潟市
  • Year and Date: 2015-07-11
• [Presentation] 扁平苔癬の問題点. ワークショップ5「口腔扁平苔癬を再考する」 (2015)
  • Author(s): 田中昭男, 伊東大典, 神部芳則, 菅原由美子, 中村誠司, 藤林孝司（日本口腔内科学会）, 小宮山一雄, 朔 敬, 田中昭男, 長谷川博雅, 前田初男（日本臨床口腔病理学会）, OLP委員会
  • Organizer: 第69回日本口腔科学会学術集会
  • Place of Presentation: 大阪国際会議場, 大阪市
  • Year and Date: 2015-05-13
• [Presentation] 口腔扁平上皮癌および正角化型異型上皮における正角化関連分子の動態 (2015)
  • Author(s): 阿部達也, 丸山 智, 山崎 学, バブカイル ハムザ, 程 クン, 朔 敬
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場, 名古屋市
  • Year and Date: 2015-04-30
• [Presentation] Tight junction molecules are involved in the neoplastic process of oral squamous epithelial cells (2015)
  • Author(s): Babkair H, Yamazaki M, Abe T, Maruyama S, Cheng J, Saku T
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場, 名古屋市
  • Year and Date: 2015-04-30
• [Presentation] Protease-activated receptor-2 modulates proliferation and invasion of oral squamous cell carcinoma cells (2015)
  • Author(s): Cheng J, Al-Eryani K, Abe T, Maruyama S, Yamazaki M, Babkair H, Saku T
  • Organizer: Asian Oncology Summit 2015
  • Place of Presentation: Shanghai International Convention Center, Shanghai, China
  • Year and Date: 2015-04-10
  • Int'l Joint Research
• [Remarks] 新潟大学大学院医歯学総合研究科口腔病理学分野 業績
  • URL: http://www.dent.niigata-u.ac.jp/patho/publications/2015.html