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Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma.

Liu JL, Chen FF, Lung J, Lo CH, Lee FH, Lu YC, Hung CH - Br. J. Cancer (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Classification of OSCCs according to LC3B and cytoplasmic expression patterns.(A) Summary of the classification of the four groups: A, B, C, and D. (B) The Kaplan–Meier curves for overall survival and disease-specific survival rates of the four groups in OSCCs. No differences in overall survival and disease-specific survival are present among the four groups in stage I and stage II OSCCs. Groups B and D exhibit unfavourable overall survival and disease-specific survival compared with Groups A and C in stage III and stage IV OSCCs.
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fig5: Classification of OSCCs according to LC3B and cytoplasmic expression patterns.(A) Summary of the classification of the four groups: A, B, C, and D. (B) The Kaplan–Meier curves for overall survival and disease-specific survival rates of the four groups in OSCCs. No differences in overall survival and disease-specific survival are present among the four groups in stage I and stage II OSCCs. Groups B and D exhibit unfavourable overall survival and disease-specific survival compared with Groups A and C in stage III and stage IV OSCCs.

Mentions: We further combined the immunoexpressions of the LC3B punctae (autophagosome marker) and cytoplasmic p62 (autophagy flux marker) to analyse the role of autophagy at early and advanced stages of OSCCs. According to their expression patterns, we classified the OSCCs into four groups: A, B, C, and D (Figure 5A). Group A (low LC3B and low p62) mimicked the basal level of autophagy in normal oral mucosas; Group B (low LC3B and high p62) represented a basal level of autophagy but impaired at late steps of the process; Group C (high LC3B and low p62) represented autophagy activation; and Group D (high LC3B and high p62) represented autophagy activation but impaired at late steps of the process. Regarding stage I and stage II OSCCs, no differences in overall survival (P=0.501) and disease-specific survival (P=0.678) were observed among the four groups. Regarding stage III and stage IV OSCCs, Groups B and D, which represented autophagy impairment under basal or activated autophagic activity, exhibited unfavourable overall survival and disease-specific survival compared with Groups A and C (Figure 5B).


Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma.

Liu JL, Chen FF, Lung J, Lo CH, Lee FH, Lu YC, Hung CH - Br. J. Cancer (2014)

Classification of OSCCs according to LC3B and cytoplasmic expression patterns.(A) Summary of the classification of the four groups: A, B, C, and D. (B) The Kaplan–Meier curves for overall survival and disease-specific survival rates of the four groups in OSCCs. No differences in overall survival and disease-specific survival are present among the four groups in stage I and stage II OSCCs. Groups B and D exhibit unfavourable overall survival and disease-specific survival compared with Groups A and C in stage III and stage IV OSCCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150268&req=5

fig5: Classification of OSCCs according to LC3B and cytoplasmic expression patterns.(A) Summary of the classification of the four groups: A, B, C, and D. (B) The Kaplan–Meier curves for overall survival and disease-specific survival rates of the four groups in OSCCs. No differences in overall survival and disease-specific survival are present among the four groups in stage I and stage II OSCCs. Groups B and D exhibit unfavourable overall survival and disease-specific survival compared with Groups A and C in stage III and stage IV OSCCs.
Mentions: We further combined the immunoexpressions of the LC3B punctae (autophagosome marker) and cytoplasmic p62 (autophagy flux marker) to analyse the role of autophagy at early and advanced stages of OSCCs. According to their expression patterns, we classified the OSCCs into four groups: A, B, C, and D (Figure 5A). Group A (low LC3B and low p62) mimicked the basal level of autophagy in normal oral mucosas; Group B (low LC3B and high p62) represented a basal level of autophagy but impaired at late steps of the process; Group C (high LC3B and low p62) represented autophagy activation; and Group D (high LC3B and high p62) represented autophagy activation but impaired at late steps of the process. Regarding stage I and stage II OSCCs, no differences in overall survival (P=0.501) and disease-specific survival (P=0.678) were observed among the four groups. Regarding stage III and stage IV OSCCs, Groups B and D, which represented autophagy impairment under basal or activated autophagic activity, exhibited unfavourable overall survival and disease-specific survival compared with Groups A and C (Figure 5B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus