Prognostic value of the autophagy markers LC3 and p62/SQSTM1 in early-stage non-small cell lung cancer

Abstract

Autophagy is a cellular degrading process that promotes tumor cell survival or cell death in cancer, depending on the progress of oncogenesis. Protein light chain 3 (LC3) and p62/SQSTM1 (p62) are associated with autophagosomal membranes that engulf cytoplasmic content for subsequent degradation. We studied LC3 and p62 expression using immunohistochemistry in a large cohort of 466 stage I/II non-small cell lung cancer (NSCLC) using a tissue microarray. We evaluated dot-like cytoplasmic expression of LC3 and dot-like, cytoplasmic and nuclear staining for p62 in relation to clinico-pathological parameters.LC3 expression correlated with all p62 patterns, as those correlated among each other (p < 0.001 each). There was no correlation with stage, age or gender. A combination of high LC3/high p62 dot-like staining (suggesting impaired autophagy) showed a trend for better outcome (p = 0.11). Interestingly, a combined low cytoplasmic/low nuclear p62 expression regardless of dot-like staining was an independent prognostic factor for longer survival (p = 0.006; HR=1.96), in addition to tumor stage (p = 0.004; HR=1.4).The autophagy markers LC3 and p62 are differentially expressed in NSCLC, pointing towards a biologically significant role. High LC3 levels seem to be linked to lower tumor aggressiveness, while high general p62 expression was significantly associated with aggressive tumor behavior.

Hepatocellular carcinomas with intracellular hyaline bodies have a poor prognosis

“…Since p62 is an autophagy substrate, a high level of p62 in the cytoplasm may indicate suppressed or defective autophagy, resulting in altered NF‐kappa B‐related gene expression and promotion of tumorigenesis . Furthermore, p62 overexpression presumably related to an autophagy defect has been found in a number of human cancers . In a recent study, a stronger cytoplasmic expression of p62 was found in HCC compared with non‐neoplastic liver.…”

“…MDBs only 17 ( related to an autophagy defect has been found in a number of human cancers. [28][29][30][31][32][33][34] In a recent study, a stronger cytoplasmic expression of p62 was found in HCC compared with non-neoplastic liver. Therefore, p62 has been proposed as a novel tumour marker for HCC.…”

MicroRNA-320 regulates autophagy in retinoblastoma by targeting hypoxia inducible factor-1α

“…As autophagy results in increased expression levels of autophagy-related proteins, four autophagy-related proteins (LC3, Beclin 1, p62 and mTOR) were analyzed in the present study to reliably evaluate the effects of miR-320 and HIF-1α on autophagy in RB tissues (29). LC3 is a specific marker of autophagosomes as it is an integral protein of the autophagosome membrane (30).…”

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

“…To clarify if autophagy-associated proteins [14] are detectable in these nuclear inclusions we looked for the presence of the proteins p62/sequestosome1, ubiquitin, LC3B, cathepsin B and cathepsin D by immunohistochemistry. Notably, p62 is also involved in several biological processes [15,16] including NFκB activity, cell proliferation [17,18], apoptosis [19], Keap1-Nrf2 system [20], DNA repair [21,22] and is associated with several cancer types [23][24][25][26][27][28][29][30][31]. In this study we investigated the occurrence of nuclear inclusions in hepatocytes of patients with HCC, characterised the inclusions by means of electron microscopy and immunohistochemistry, and explored if these inclusions have any impact on patient survival.…”