Ieni Antonio, Cardia Roberta, Giuffrè Giuseppe, Rigoli Luciana, Caruso Rosario Alberto, Tuccari Giovanni
Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, 98123 Messina, Italy.
Cancers (Basel). 2019 Mar 19;11(3):389. doi: 10.3390/cancers11030389.
In neoplastic conditions, autophagy may act as a tumor suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumor growth. Although ultrastructural analysis has been considered the traditional method to identify autophagy, some proteins such as microtubule-associated protein 1 light chain 3 (LC3A/B), Beclin-1 and activating molecule in Beclin-1-regulated autophagy protein-1 (AMBRA-1) may be considered as markers of autophagy-assisted cancerogenesis. Herein, we analyzed a cohort of advanced tubular gastric adenocarcinomas by the abovementioned immunohistochemical antisera; through immunohistochemistry, autophagy (A-IHC) is diagnosed when at least two out of the three proteins are positive in the samples. Immunostaining for LC3A/B, Beclin-1, and AMBRA-1 was exclusively found in neoplastic elements, but not in surrounding stromal cells. In detail, LC3A/B and Beclin 1 were expressed both in the cytoplasm and in the nucleus of the cancer cells, while AMBRA-1 was preferentially localized in the nucleus, mainly in high grade cases. LC3A/B, Beclin 1, and AMBRA-1 expression were positive in 18 (56.2%), 17 (53.1%), and 12 (37.5%) cases, respectively. The sensibility and specificity of LC3A/B and Beclin-1 ranged from 81.25% to 93.75%, with high efficiency (90.63%) for Beclin-1. Moreover, the ultrastructural autophagic index (AI) was also available in all cases. All high-grade cases documented a Ki-67 labelling index (LI) ≥ 30%, even if three low-grade cases revealed a high Ki-67 value; p53 positivity was encountered in 21/32 (65.62%) of cases, independently of the tumor grade. A statistically significant correlation among A-IHC and clinicopathological parameters such as grade, stage, clinical course, Ki-67 LI and AI was revealed. Univariate analysis documented a significant -value for the same autophagic variables. Additionally, multivariate survival analysis identified the grade, AI and A-IHC as independent significant variables. Finally, the overall survival curves of all cases of gastric tubular adenocarcinoma were greatly dependent on A-IHC. Therefore, we suggest that autophagic-related proteins might be considered promising predictive prognostic factors of advanced gastric cancer. Further investigations may be required to determine whether new targeted therapies should be addressed to autophagy-related proteins.
在肿瘤性疾病中，自噬可能作为一种肿瘤抑制机制，避免受损蛋白质和细胞器的积累，也可能作为一种促进肿瘤生长的细胞存活机制。尽管超微结构分析一直被认为是识别自噬的传统方法，但一些蛋白质，如微管相关蛋白1轻链3（LC3A/B）、Beclin-1和Beclin-1调节的自噬蛋白1激活分子（AMBRA-1），可被视为自噬辅助肿瘤发生的标志物。在此，我们用上述免疫组化抗血清分析了一组晚期管状胃腺癌；通过免疫组化，当样本中三种蛋白质中的至少两种呈阳性时，诊断为自噬（A-IHC）。LC3A/B、Beclin-1和AMBRA-1的免疫染色仅在肿瘤细胞中发现，而在周围基质细胞中未发现。具体而言，LC3A/B和Beclin 1在癌细胞的细胞质和细胞核中均有表达，而AMBRA-1主要定位于细胞核，主要在高级别病例中。LC3A/B、Beclin 1和AMBRA-1表达阳性的病例分别为18例（56.2%）、17例（53.1%）和12例（37.5%）。LC3A/B和Beclin-1的敏感性和特异性范围为81.25%至93.75%，Beclin-1的效率较高（90.63%）。此外，所有病例均有超微结构自噬指数（AI）。所有高级别病例的Ki-67标记指数（LI）≥30%，即使有三例低级别病例的Ki-67值较高；21/32（65.62%）的病例中出现p53阳性，与肿瘤级别无关。A-IHC与分级、分期、临床病程、Ki-67 LI和AI等临床病理参数之间存在统计学显著相关性。单因素分析显示相同自噬变量的p值具有显著性。此外，多因素生存分析确定分级、AI和A-IHC为独立的显著变量。最后，所有胃管状腺癌病例的总生存曲线在很大程度上依赖于A-IHC。因此，我们建议自噬相关蛋白可能是晚期胃癌有前景的预测预后因素。可能需要进一步研究以确定是否应针对自噬相关蛋白进行新的靶向治疗。
