CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways

Background/Aims: Chloride intracellular channel 1 (CLIC1), which is a member of the chloride channel protein family, is associated with various human tumors. Recent studies have shown that CLIC1 is involved in the occurrence and development of gastric cancer (GC). However, the exact mechanism remains unclear in GC. Methods: Effects of CLIC1 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated by analysing 54 patients with GC, as well as human gastric cell lines SGC-7901 and MGC-803, utilizing proteomics, RT-PCR, Western blotting, flow cytometry, Cell invasion and migration assays and xenograft tumor models. Results: Our study shows that CLIC1 knockdown by targeted-siRNA markedly inhibits GC cell invasion and migration and induces apoptosis in vitro. In total, 54 differentially expressed proteins were identified in GC cells SGC-7901 after CLIC1 silencing by isobaric tags for relative isotope labeled and absolute quantitation (iTRAQ) technology, including integrin alpha 1 (ITG alpha 1) and ITG alpha 3. The expression levels of ITG alpha 3, ITG alpha v, ITG beta 1 and Bcl-2 mRNA and protein were decreased significantly in GC cells after CLIC1 knockdown; ITGa1 and Fas were upregulated, but the level of survivin was not significantly different. GC growth and metabolism were decreased in vivo after CLIC1 silencing, but apoptosis was markedly increased. Further study showed that the expression levels of ITG alpha 3, ITG alpha v and ITG beta 1, as well as AKT-phosphorylation, ERK-phosphorylation and p38-phosphorylation, were reduced in vivo after CLIC1 knockdown, while ITG alpha 1 was upregulated. Conclusions: We speculate that CLIC1 may play an important role in the progression of GC, and its mechanism may be related to the regulation of integrin family proteins, which leads to the sequential regulation of the PI3K/AKT, MAPK/ERK and MAPK/p38 pathways. (C) 2018 The Author(s) Published by S. Karger AG, Basel