Altered desmoplakin expression at transcriptional and protein levels provides prognostic information in human oropharyngeal cancer.
Desmoplakin, a desmosomal component, is a key protein involved in cell-cell adhesion. Down-regulation of desmosomal proteins is associated with the invasive and metastatic ability of tumor cells. We examined 37 cases of human primary oropharyngeal squamous cell carcinomas lacking overt distant metastases to gain further insights on the potential role of desmoplakin in oral cancer. Desmoplakin expression was evaluated using reverse transcriptase-polymerase chain reaction and immunohistochemistry on frozen unfixed sections. Western blotting was performed to characterize the relative expression levels for each of the 2 desmoplakin protein isoforms, I and II. Desmoplakin expression was compared with histopathological grade, clinical stage, and patient outcome. Desmoplakin expression was prominent in highly differentiated tumors and reduced or absent in poorly differentiated tumors that developed distant metastases within the 3 years of follow-up period. Desmoplakin mRNA levels tracked with protein levels, suggesting that lack of desmoplakin protein expression is due to down-regulation of mRNA expression at the transcription level. Western blot analysis demonstrated that the 2 desmoplakin isoforms displayed different patterns of subcellular distribution in tumors, with the desmoplakin II detected only in patients in which desmoplakin immunoreactivity displayed an abnormal cytoplasmic localization. Our findings suggest that down-regulation of desmoplakin expression may represent a useful marker for evaluating the risk of distant metastasis formation in oropharyngeal squamous cell carcinomas. Interestingly, desmoplakin II was detected only in tumors associated with a poor clinical outcome, suggesting a potential specific function for this isoform in oral carcinogenesis. Characterizing DSP expression may improve evaluation risk of distant metastasis formation in oral cancer patients.
Papagerakis
Silvana
S
Laboratoire de Biologie Orofaciale et Pathologie, INSERM UMRS872, Université Paris 7, Centre de Recherche des Cordeliers, Paris, 75006 France. silvanap@umich.edu
Shabana
Al-Hassan
AH
Pollock
Brad H
BH
Papagerakis
Petros
P
Depondt
Joël
J
Berdal
Ariane
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002448:Cell Adhesion; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D011379:Prognosis; D011446:Prospective Studies; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D016019:Survival Analysis; D013997:Time Factors; D014158:Transcription, Genetic; D047368:Tumor Burden
D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm