Das L, Kokate S B, Dixit P, Rath S, Rout N, Singh S P, Crowe S E, Bhattacharyya A
School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Jatni, Odisha, India.
Department of Oncopathology, Acharya Harihar Regional Cancer Centre, Cuttack, Odisha, India.
Oncogenesis. 2017 May 8;6(5):e327. doi: 10.1038/oncsis.2017.26.
β-catenin has two different cellular functions: intercellular adhesion and transcriptional activity. The E3 ubiquitin ligase Siah1 causes ubiquitin-mediated degradation of the cytosolic β-catenin and therefore, impairs nuclear translocation and oncogenic function of β-catenin. However, the effect of Siah1 on the cell membrane bound β-catenin has not been studied. In this study, we identified that the carcinogenic bacterium H. pylori increased ETS2 transcription factor-mediated Siah1 protein expression in gastric cancer cells (GCCs) MKN45, AGS and Kato III. Siah1 protein level was also noticeably higher in gastric adenocarcinoma biopsy samples as compared to non-cancerous gastric epithelia. Siah1 knockdown significantly decreased invasiveness and migration of H. pylori-infected GCCs. Although, Siah1 could not increase degradation of the cytosolic β-catenin and its nuclear translocation, it enhanced degradation of the membrane-bound β-catenin in the infected GCCs. This loss of membrane-bound pool of β-catenin was not associated with the proteasomal degradation of E-cadherin. Thus, this work delineated the role of Siah1 in increasing invasiveness of H. pylori-infected GCCs.
β-连环蛋白具有两种不同的细胞功能：细胞间黏附作用和转录活性。E3泛素连接酶Siah1可导致胞质β-连环蛋白发生泛素介导的降解，因此会损害β-连环蛋白的核转位及致癌功能。然而，Siah1对细胞膜结合型β-连环蛋白的影响尚未得到研究。在本研究中，我们发现致癌细菌幽门螺杆菌可增加胃癌细胞（GCCs）MKN45、AGS和Kato III中ETS2转录因子介导的Siah1蛋白表达。与非癌性胃上皮相比，胃腺癌活检样本中的Siah1蛋白水平也明显更高。敲低Siah1可显著降低幽门螺杆菌感染的GCCs的侵袭性和迁移能力。尽管Siah1不能增加胞质β-连环蛋白的降解及其核转位，但它可增强感染的GCCs中膜结合型β-连环蛋白的降解。β-连环蛋白膜结合池的这种减少与E-钙黏蛋白的蛋白酶体降解无关。因此，这项工作阐明了Siah1在增加幽门螺杆菌感染的GCCs侵袭性中的作用。
