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Immunohistochemical Expression of Autophagy-Related Proteins in Advanced Tubular Gastric Adenocarcinomas and Its Implications

Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98123 Messina, Italy
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Cancers 2019, 11(3), 389; https://doi.org/10.3390/cancers11030389
Received: 25 February 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)
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Abstract

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 p-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. View Full-Text
Keywords: autophagy; immunohistochemistry; gastric cancer; tubular adenocarcinoma; grading autophagy; immunohistochemistry; gastric cancer; tubular adenocarcinoma; grading
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Ieni, A.; Cardia, R.; Giuffrè, G.; Rigoli, L.; Caruso, R.A.; Tuccari, G. Immunohistochemical Expression of Autophagy-Related Proteins in Advanced Tubular Gastric Adenocarcinomas and Its Implications. Cancers 2019, 11, 389.

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