Yoon Ju-Yoon, Brezden-Masley Christine, Streutker Catherine J
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Department of Pathology, St. Michael's Hospital, Toronto, ON, Canada.
Front Oncol. 2021 Mar 30;11:555614. doi: 10.3389/fonc.2021.555614. eCollection 2021.
Gastric/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.
Autophagic 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.
Dysplastic 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 LC3B/p62 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 -value = 0.0396).
Our 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.
胃/胃食管交界（GEJ）腺癌是一种异质性疾病，病因多样，肿瘤涵盖一系列组织学和分子亚型。“自噬”包括两个相关但不同的稳态过程，可在不利条件下促进细胞存活，即巨自噬和伴侣介导的自噬。越来越多的证据表明自噬可能在肿瘤发生中发挥作用。
利用针对自噬途径中特定蛋白质（p62、LAMP2A、LC3B）的免疫组织化学方法，在胃/GEJ腺癌固有的异质性背景下检测自噬途径。我们检查了正常和发育异常胃黏膜的全切片以及腺癌组织微阵列。
与正常胃上皮相比，发育异常的胃上皮以核p62频繁表达和LAMP2A异常表达为特征。检查胃腺癌中LC3B/细胞质p62免疫反应性模式显示，LC3B/p62染色占主导模式（56/86，65.1%），这与活跃但受损的巨自噬相关。LC3B/细胞质p62染色模式与肿瘤分级、组织类型或近似的TCGA分子亚型之间未发现统计学上的显著关联。LAMP2A、核p62及其染色模式在整个队列中也存在异质性，但未发现统计学上的显著关联。这三种蛋白质的预后意义有限，然而高核p62水平与较差的总生存期相关（对数秩检验P值 = 0.0396）。
我们的数据证明了胃上皮中自噬蛋白的动态性质，并且我们将在胃/GEJ腺癌中观察到的生物学异质性扩展至包括自噬。
