Abstract
BackgroundAutophagy 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.MethodsIn 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.ResultsSurvival 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.ConclusionsImmunohistochemical 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12957-016-0946-x) contains supplementary material, which is available to authorized users.
Highlights
Autophagy is a cellular pathway that regulates transportation of cytoplasmic macromolecules and organelles to lysosomes for degradation
We investigated the potential prognostic value of the autophagyrelated proteins Beclin-1, p62, light chain 3 (LC3) and uncoordinated 51-like kinase 1 (ULK1) in a cohort of colorectal cancer (CRC) specimens with a focus on patients with an unfavourable outcome due to Union internationale contre le cancer (UICC) stage III/IV CRC treated with chemotherapy and/or Kirsten RAS (KRAS)-mutated CRCs
Representative staining examples of p62, Beclin-1, LC3 and ULK1 are shown in Figs. 1, 2, 3 and 4
Summary
Autophagy is a cellular pathway that regulates transportation of cytoplasmic macromolecules and organelles to lysosomes for degradation. 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. Macroautophagy, referred to as autophagy, is a process that allows cells to deliver intracellular proteins, lipids and organelles to lysosomes where degradation can take place [1]. The intracellular material is removed from the lysosomal compartment and recycling occurs in the cytoplasm [2]. LC3, p62, Beclin-1 and uncoordinated (UNC) 51-like kinase 1 (ULK1) are central autophagy-related proteins involved in the autophagy flux. LC3 (microtubule-associated protein 1 light chain 3) is a well-established marker of autophagy activity in cancer cells [5]. Measurement of LC3 expression by immunohistochemistry is a frequently used method to reliably quantify autophagosome formation [7]
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