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

Abstract

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 α1 (ITGα1) and ITGα3. The expression levels of ITGα3, ITGαv, ITGβ1 and Bcl-2 mRNA and protein were decreased significantly in GC cells after CLIC1 knockdown; ITGα1 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 ITGα3, ITGαv and ITGβ1, as well as AKT-phosphorylation, ERK-phosphorylation and p38-phosphorylation, were reduced in vivo after CLIC1 knockdown, while ITGα1 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.

Expression of CLIC1 as a potential biomarker for oral squamous cell carcinoma: a preliminary study

“…CLIC1 has been reported to be upregulated in human malignant tumors of the colon, brain, liver, stomach, and lung. 14 , 22 , 24 , 26 , 27 It was evaluated to be the most penetrating receptor among commonly dysregulated proteins within three sarcomas. 23 This protein plays an important role in the metastasis of colonic cancer.…”

“… 31 What is more, CLIC1 may be correlated with the regulation of integrin-family proteins, which leads to subsequent regulation of the PI3K–AKT, MAPK–p38, and MAPK–ERK pathways. 14 To evaluate the biological function of CLIC1 in OSCC pathogenesis further, we compared CLIC1 with tumor-associated genes using PCR. We found that CLIC1 was relevant to a variety of tumor genes, especially PA28B , MMP2, and MMP13, whereas PA28B and matrix metalloproteinases (MMPs) played an important role in tumor metastasis and invasiveness.…”

Upregulated lncRNA-UCA1 contributes to metastasis of bile duct carcinoma through regulation of miR-122/CLIC1and activation of the ERK/MAPK signaling pathway

“…The chloride intracellular channel 1 (CLIC1) is a member of the CLIC family. Additionally, it is also the most studied one in the family [17]. The effects of CLIC1 have been explored and reported in human cancers.…”

<p>Integrin α5/ITGA5 Promotes The Proliferation, Migration, Invasion And Progression Of Oral Squamous Carcinoma By Epithelial–Mesenchymal Transition</p>

“…Integrins are a family of transmembrane receptors; they form heterodimeric complexes composed of α and β subunits. [10][11][12][13] The 18α and 8β subunits are members of approximately 24 different Integrin receptors, each of which is capable of binding to specific ligands. They function in specific signal transduction pathways and in cell-cell adhesion and the adhesion between cells and the ECM.…”