title: Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma.
abstract: BACKGROUND
  Autophagy is a programmed cell survival mechanism that has a key role in both physiologic and pathologic conditions. The relationship between autophagy and cancer is complex because autophagy can act as either a tumour suppressor or as a tumour promoter. The role of autophagy in oral squamous cell carcinoma (OSCC) is controversial. Several studies have claimed that either a high or low expression of autophagy-related proteins was associated with poor prognosis of OSCCs. The aims of the study were to compare autophagy in OSCCs, verrucous hyperplasias, and normal oral mucosas, and to inspect the prognostic role of autophagy in OSCCs.
  
  
  METHODS
  We used the autophagosome marker, LC3B, and autophagy flux marker, p62/SQSTM1 (p62), by using immunohistochemistry, and examined p62 mRNA by RNA in situ hybridization, to evaluate autophagy in 195 OSCCs, 47 verrucous hyperplasias, and 37 normal oral mucosas. The prognostic roles of LC3B and p62 protein expressions in OSCCs were investigated.
  
  
  RESULTS
  We discovered that the normal oral mucosa exhibited limited LC3B punctae and weak cytoplasmic p62 staining, whereas the OSCCs exhibited a marked increase in LC3B punctae and cytoplasmic p62 expression. The expression pattern of LC3B and cytoplasmic p62 of the verrucous hyperplasias were between normal oral mucosas and OSCCs. The normal oral mucosas, verrucous hyperplasias, and OSCCs presented no differences in nuclear p62 expression and the p62 mRNA level. p62 mRNA expression was elevated in a minority of cases. High p62 mRNA expression was associated with high p62 protein expression in the cytoplasm. Increased LC3B punctae, high cytoplasmic p62, and low nuclear p62 expressions in OSCCs were associated with aggressive clinicopathologic features and unfavourable prognosis. In addition, low nuclear p62 expression was an independent prognostic factor for overall and disease-specific survival rates. Furthermore, we disclosed that high cytoplasmic p62 expression accompanied with either a low or high LC3B expression, which indicated autophagy impairment under basal or activated autophagic activity, was associated with aggressive behaviour in advanced OSCCs.
  
  
  CONCLUSIONS
  We suggested that autophagy was altered during cancer initiation and progression. Autophagy impairment contributed to cancer progression in advanced OSCCs.
authors.affiliation: 1] Department of Pathology, St. Martin De Porres Hospital, No. 565, Sector 2, Daya Road, Chiayi City 600, Taiwan [2] Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Guishan Township, Taoyuan County 333, Taiwan.
authors.forename: J-L
authors.initials: JL
authors.lastname: Liu
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital at Chiayi, No. 6, W. Sector, Jiapu Road, Puzi City, Chiayi County 613, Taiwan.
authors.forename: F-F
authors.initials: FF
authors.lastname: Chen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital at Chiayi, No. 6, W. Sector, Jiapu Road, Puzi City, Chiayi County 613, Taiwan.
authors.forename: J
authors.initials: J
authors.lastname: Lung
authors.affiliation: Department of Oral and Maxillofacial Surgery, St. Martin De Porres Hospital, No. 565, Sector 2, Daya Road, Chiayi City 600, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lo
authors.affiliation: Department of Oral and Maxillofacial Surgery, St. Martin De Porres Hospital, No. 565, Sector 2, Daya Road, Chiayi City 600, Taiwan.
authors.forename: F-H
authors.initials: FH
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology, St. Martin De Porres Hospital, No. 565, Sector 2, Daya Road, Chiayi City 600, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Lu
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Guishan Township, Taoyuan County 333, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Hung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D001343:Autophagy / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D000071456:Sequestosome-1 Protein; D015996:Survival Rate
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein