title: Hemophagocytosis-mediated keratinization in oral carcinoma in situ and squamous cell carcinoma: a possible histopathogenesis of keratin pearls.
abstract: Although the histopathogenetic process of keratin pearls is still poorly understood, acceleration of keratinization in squamous cell carcinoma (SCC) cells may represent one possible therapeutic avenue. Based on our histopathological observations, we have hypothesized that SCC cells are keratinized by phagocytosis of extravasated erythrocytes. To confirm this hypothesis, we firstly examined immature keratin pearls in oral carcinoma in situ (CIS) and mature ones in SCC by immunohistochemistry. Concentric dyskeratotic cells in CIS keratin pearls became positive for keratin (K) 10, K17, heme oxygenase-1 (HO-1), or protease activated receptor-2 (PAR-2), a candidate regulator for hemophagocytosis. When ZK-1 cells, an SCC cell system, were incubated with human peripheral blood erythrocytes, or with crude and purified hemoglobins (Hbs), their erythro-hemophagocytotic activities were confirmed by immunofluorescence. Immunofluorescence signals for K10, K17, and HO-1 were enhanced due to hemophagocytosis in time-dependent manners. mRNA expression levels for the three molecules were most enhanced by purified Hb, followed by crude Hb and erythrocytes. K17/K10 mRNA expression levels were more elevated when PAR-2 was activated in ZK-1 cells. The results indicated that immature and mature keratin pearls in CIS and SCC were generated by oxidative stresses derived from erythro-hemophagocytosis, which might mediate HO-1 expression and be regulated by PAR-2. Thus, hemorrhage from the rupture of blood vessels can be one of the triggers for keratin pearl formation in oral CIS and SCC.
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Chuo-Ku, Niigata, Japan.
authors.forename: Kamal
authors.initials: K
authors.lastname: Al-Eryani
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Abé
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuneki
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essa
authors.forename: Hamzah
authors.initials: H
authors.lastname: Babkair
authors.forename: Takashi
authors.initials: T
authors.lastname: Saku
mesh_terms: D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D053550:Keratin-10 / Q000235:genetics / Q000378:metabolism*; D053537:Keratin-17 / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D053537:Keratin-17; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D053550:Keratin-10; D051547:Heme Oxygenase-1