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Expression Analysis of Autophagy Related Markers LC3B, p62 and HMGB1 Indicate an Autophagy-Independent Negative Prognostic Impact of High p62 Expression in Pulmonary Squamous Cell Carcinomas

Langer, Rupert, Neppl, Christina, Keller, Manuel D., Schmid, Ralph A., Tschan, Mario P., Berezowska, Sabina·2018·Cancers
DOI 10.3390/cancers10090281PMC PMC6162479
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Abstract

Autophagy is involved in maintaining cellular homeostasis under stress conditions. It also plays an important role in various diseases including cancer. Pulmonary squamous cell carcinomas (pSQCC) at present lack targetable molecular alterations, and demand alternative therapeutic options. We assessed the expression levels of autophagy related proteins LC3B, p62, and HMGB1 in 271 primary resected pSQCC by immunohistochemistry, in correlation with clinical and pathological parameters, as a rationale for a potential autophagy directed therapy. LC3B, p62, and HMGB1 staining showed various patterns. LC3Bhighp62low levels, suggested to indicate intact activated autophagy, were associated with prolonged disease specific survival (DSS) and LC3Bhighp62high levels, indicating activated but late stage impaired autophagy, with shorter DSS (p = 0.024). p62high expression regardless of LC3B, however, showed an even stronger association with shorter DSS (p = 0.015) and was also an independent negative prognostic factor in multivariate analysis (HR = 2.99; 95% CI 1.38–6.52; p = 0.006). HMGB1 expression correlated neither with the expression of LC3B and p62, nor with patients’ outcome. Different states of autophagy characterized by distinct p62 and LC3B expression patterns may be linked to patient’s prognosis in pSQCC. Our results, however, point also to an autophagy independent role of p62 with an even more pronounced prognostic impact compared to autophagy related p62.

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Crossref · 10.3390/cancers10090281

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Figure 1 Examples of immunohistochemical stainings; (A) LC3B low, (B) LC3B high, (C) p62 low (any cellular compartment), (D) p62 cytoplasmic low, (E) p62 cytoplasmic/dot like high, nuclear low, (F) p62 cytoplasmic/dot like low, nuclear high, (G) HMGB1 low, (H) HMGB1 high. Objective magnification, 40×.
Figure 1 Examples of immunohistochemical stainings; (A) LC3B low, (B) LC3B high, (C) p62 low (any cellular compartment), (D) p62 cytoplasmic low, (E) p62 cytoplasmic/dot like high, nuclear low, (F) p62 cytoplasmic/dot like low, nuclear high, (G) HMGB1 low, (H) HMGB1 high. Objective magnification, 40×.CC BY · PubMed Central
Figure 2 LC3B/p62 patterns and CD8+Tumor-infiltrating Lymphocytes. LL = LC3Blowp62low; LH = LC3Blowp62high; HL = LC3Bhighp62low; HH = LC3Bhighp62high, ° indicate outliers.
Figure 2 LC3B/p62 patterns and CD8+Tumor-infiltrating Lymphocytes. LL = LC3Blowp62low; LH = LC3Blowp62high; HL = LC3Bhighp62low; HH = LC3Bhighp62high, ° indicate outliers.CC BY · PubMed Central
Figure 3 Survival curves (disease free survival) for expression of autophagy related proteins (A) LC3B; (B) p62 dot-like/cytoplasmic; (C) p62 nuclear; (D) HMGB1.
Figure 3 Survival curves (disease free survival) for expression of autophagy related proteins (A) LC3B; (B) p62 dot-like/cytoplasmic; (C) p62 nuclear; (D) HMGB1.CC BY · PubMed Central
Figure 4 Survival curves for combination LC3B/p62 categorization into four subgroups: LL = LC3Blowp62low; LH = LC3Blowp62high; HL = LC3Bhighp62low; HH = LC3Bhighp62high; (A) disease specific survival (DSS); (B) time to relapse (TTR).
Figure 4 Survival curves for combination LC3B/p62 categorization into four subgroups: LL = LC3Blowp62low; LH = LC3Blowp62high; HL = LC3Bhighp62low; HH = LC3Bhighp62high; (A) disease specific survival (DSS); (B) time to relapse (TTR).CC BY · PubMed Central

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Citations

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Metadata

Authors
Langer, R., Neppl, C., Keller, M. D., Schmid, R. A., Tschan, M. P., & Berezowska, S.
Affiliations
  • Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland
  • Division of General Thoracic Surgery, Inselspital University Hospital Bern, 3010 Bern, Switzerland
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2018-08-21
Volume
10
Issue
9
Pages
281
ISSN
2072-6694
DOI
10.3390/cancers10090281
PMC
PMC6162479
Cited by
17
References
3
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Bernische Krebsliga (no number)

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