Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", 15310 Athens, Greece.
Int J Mol Sci. 2017 Sep 7;18(9):1920. doi: 10.3390/ijms18091920.
Autophagy is a catabolic process that preserves cellular homeostasis. Its exact role during carcinogenesis is not completely defined. Specifically in head and neck cancer, such information from clinical settings that comprise the whole spectrum of human carcinogenesis is very limited. Towards this direction, we examined the in situ status of the autophagy-related factors, Beclin-1, microtubule-associated protein 1 light chain 3, member B (LC3B) and sequestosome 1/p62 (p62) in clinical material covering all histopathological stages of human head and neck carcinogenesis. This material is unique as each panel of lesions is derived from the same patient and moreover we have previously assessed it for the DNA damage response (DDR) activation status. Since Beclin-1, LC3B and p62 reflect the nucleation, elongation and degradation stages of autophagy, respectively, their combined immunohistochemical (IHC) expression profiles could grossly mirror the autophagic flux. This experimental approach was further corroborated by ultrastructural analysis, applying transmission electron microscopy (TEM). The observed Beclin-1/LC3B/p62 IHC patterns, obtained from serial sections analysis, along with TEM findings are suggestive of a declined authophagic activity in preneoplastic lesions that was restored in full blown cancers. Correlating these findings with DDR status in the same pathological stages are indicative of: (i) an antitumor function of autophagy in support to that of DDR, possibly through energy deprivation in preneoplastic stages, thus preventing incipient cancer cells from evolving; and (ii) a tumor-supporting role in the cancerous stage.
自噬是一种维持细胞内稳态的分解代谢过程。其在致癌过程中的确切作用尚未完全确定。特别是在头颈部癌症中，来自包含人类致癌过程全貌的临床环境的此类信息非常有限。为此，我们检查了自噬相关因子 Beclin-1、微管相关蛋白 1 轻链 3B（LC3B）和自噬溶酶体相关蛋白 1/62（p62）在临床标本中的原位状态，这些标本涵盖了人类头颈部致癌过程的所有组织病理学阶段。这些材料是独一无二的，因为每一组病变都来自同一位患者，而且我们之前已经评估了它们的 DNA 损伤反应（DDR）激活状态。由于 Beclin-1、LC3B 和 p62 分别反映了自噬的核形成、延伸和降解阶段，因此它们的联合免疫组织化学（IHC）表达谱可以大体反映自噬通量。这种实验方法通过应用透射电子显微镜（TEM）进行超微结构分析得到了进一步证实。从连续切片分析获得的观察到的 Beclin-1/LC3B/p62 IHC 模式以及 TEM 结果表明，在癌前病变中自噬活性下降，但在完全发展的癌症中得到恢复。将这些发现与同一病理阶段的 DDR 状态相关联表明：（i）自噬具有抗肿瘤功能，支持 DDR，可能通过在癌前阶段剥夺能量，从而阻止早期癌细胞的发展；（ii）在癌症阶段具有肿瘤支持作用。
