title: Subtypes of cervical adenosquamous carcinomas classified by EpCAM expression related to radiosensitivity.
abstract: Adenosquamous carcinoma (ASC) is a relatively uncommon histological subtype of cervical cancer (CC). A point of controversy is the relative prognosis of ASC compared to squamous cell carcinoma (SCC). We hypothesized that ASC could be classified into two intrinsic molecular subtypes with different outcomes. We examined 143 biopsy samples of CC patients to identify a molecule for classification using microarray expression analysis and immunohistochemical analysis (IHA). We found specific expression profiles of candidate genes that distinguished two clusters. All adenocarcinoma (AC) patients were classified into one cluster, and most SCC patients fell into the other cluster. ASC patients were classified across the two clusters, which showed significantly different prognoses. The SCC-like expression signature comprised ANXA8, CK5, IFI16, and nectin-1; and the AC-like signature comprised EpCAM, and TMEM98. These signature-specific genes hypothetically indicated specific pathways by ontological analysis. The AC-like signature suggested an epithelial-mesenchymal transition and activated β-catenin pathway, while the SCC-like signature suggested keratinocyte differentiation, HPV infection, and p53-mediated apoptosis. IHA revealed that positive expression of the most promising protein, EpCAM, was significantly associated with poor prognosis. In addition, the inhibition of EpCAM expression using siRNA significantly increased radiation-induced cell death in the cervical cell line, ME-180. In conclusion, we identified two possible ASC subtypes associated with different expression profiles and different prognoses. This work provides a novel set of genes that could be used as independent prognostic markers and therapy targets.
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Imadome
authors.forename: Mayumi
authors.initials: M
authors.lastname: Iwakawa
authors.forename: Miyako
authors.initials: M
authors.lastname: Nakawatari
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Fujita
authors.forename: Shingo
authors.initials: S
authors.lastname: Kato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ohno
authors.forename: Etsuko
authors.initials: E
authors.lastname: Nakamura
authors.forename: Yu
authors.initials: Y
authors.lastname: Ohkubo
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tamaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kiyohara
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000378:metabolism / Q000473:pathology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D018196:Carcinoma, Adenosquamous / Q000145:classification* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000145:classification* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000145:classification* / Q000378:metabolism / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D012333:RNA, Messenger; D034741:RNA, Small Interfering