title: Prognostic relevance of autophagy-related markers LC3, p62/sequestosome 1, Beclin-1 and ULK1 in colorectal cancer patients with respect to KRAS mutational status.
abstract: Autophagy is a cellular pathway that regulates transportation of cytoplasmic macromolecules and organelles to lysosomes for degradation. Autophagy is involved in both tumorigenesis and tumour suppression. Here we investigated the potential prognostic value of the autophagy-related proteins Beclin-1, p62, LC3 and uncoordinated (UNC) 51-like kinase 1 (ULK1) in a cohort of colorectal cancer (CRC) specimens.
  
  
  
  In this study, we analysed the immunoexpression of the autophagy-related proteins p62, LC3, Beclin-1 and ULK1 in 127 CRC patients with known KRAS mutational status and detailed clinical follow-up.
  
  
  
  Survival analysis of p62 staining showed a significant correlation of cytoplasmic (not nuclear) p62 expression with a favourable tumour-specific overall survival (OS). The prognostic power of cytoplasmic p62 was found in the KRAS-mutated subgroup but was lost in the KRAS wildtype subgroup. Survival analysis of Beclin-1 staining did not show an association with OS in the complete cohort. LC3 overexpression demonstrated a slight, though not significant, association with decreased OS. Upon stratifying cases by KRAS mutational status, nuclear (not cytoplasmic) Beclin-1 staining was associated with a significantly decreased OS in the KRAS-mutated subgroup but not in the KRAS wildtype CRCs. In addition, LC3 overexpression was significantly associated with decreased OS in the KRAS-mutated CRC subgroup. ULK1 expression was not correlated to survival.
  
  
  
  Immunohistochemical analyses of LC3, p62 and Beclin-1 may constitute promising novel prognostic markers in CRC, especially in KRAS-mutated CRCs. This strategy might help in identifying high-risk patients who would benefit from autophagy-related anticancer drugs.
authors.affiliation: Institute of Pathology, Mühlenstrasse 31, 45659, Recklinghausen, Germany. kjschmitz@pathologie-re.de.|Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, 45147, Germany. kjschmitz@pathologie-re.de.
authors.forename: Klaus Juergen
authors.initials: KJ
authors.lastname: Schmitz
authors.affiliation: Department of Senology, Prosper Hospital Recklinghausen, Mühlenstrasse 27, 45659, Recklinghausen, Germany.
authors.forename: Ceflije
authors.initials: C
authors.lastname: Ademi
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, 45147, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bertram
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, 45147, Germany.
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, 45147, Germany.
authors.forename: Hideo Andreas
authors.initials: HA
authors.lastname: Baba
mesh_terms: D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism*; D000071186:Beclin-1 / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: C491997:BECN1 protein, human; D000071186:Beclin-1; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Autophagy; Beclin-1; Colorectal cancer; LC3; ULK1; p62