Abstract
Background and AimGastric/gastroesophageal junction (GEJ) adenocarcinoma is a heterogeneous disease, with various etiologies and with tumors encompassing a spectrum of histologic and molecular subtypes. “Autophagy” includes two related but distinct homeostatic processes that promote cell survival under adverse conditions, namely macro- and chaperone-mediated autophagy. There is increasing evidence of the roles autophagy may play in tumorigenesis.MethodsAutophagic pathways were examined in the context of the heterogeneity intrinsic to gastric/GEJ adenocarcinoma, utilizing immunohistochemistry targeting specific proteins within the pathways (p62, LAMP2A, LC3B). We examined whole sections of normal and dysplastic gastric mucosa, as well as a tissue microarray of adenocarcinomas.ResultsDysplastic gastric epithelium was marked by frequent nuclear p62 and aberrant LAMP2A expression compared to normal. Examining the pattern of LC3B/cytoplasmic p62 immuno-reactivity in gastric adenocarcinoma demonstrated a predominant pattern of LC3BHigh/p62High staining (56/86, 65.1%), which has been previously associated with active, but impaired macroautophagy. There were no statistically significant associations seen between LC3B/cytoplasmic p62 staining patterns with tumor grade, histotype, or approximated TCGA molecular subtype. LAMP2A and nuclear p62 and staining patterns were also heterogeneous across the cohort, but with no statistically significant associations seen. The prognostic significance of the three proteins was limited, however high nuclear p62 levels were associated with worse overall survival (log-rank p-value = 0.0396).ConclusionOur data demonstrate the dynamic nature of autophagic proteins in the gastric epithelium, and we expand the biological heterogeneity observed in gastric/GEJ adenocarcinoma to include autophagy.
Highlights
Metabolic homeostasis is maintained by several pathways, including autophagy
We aimed to examine the significance of autophagy in gastric cancer, while addressing the heterogeneity both in autophagy and in gastric cancer
We examined the levels of three autophagy-related proteins, MAP1LC3B (LC3B), p62, and LAMP2A, by IHC in the normal-to-carcinoma spectrum, and we describe their heterogeneous expression patterns in our cohort of gastric/gastro-esophageal junction (GEJ) adenocarcinoma
Summary
Autophagy is a cellular process which allows the cell to remove damaged components and to “recycle” normal cytoplasmic constituents. This is an important protective mechanism in epithelial cell homeostasis and cell survival; for example, inhibiting autophagy in an animal model of ethanol exposure results in increased gastric epithelial cell death and ulceration [1]. Macroautophagy involves sequestration of different cytosolic constituents and digestion of the content by autophago-lysosomes [2]. Macroautophagy involves both the conversion of LC3B to LC3B-II as well as consumptive degradation of various contents in and on the autophagolysosome, including p62. There is increasing evidence of the roles autophagy may play in tumorigenesis
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