TRPC1/3/6 inhibition attenuates the TGF‐β1‐induced epithelial–mesenchymal transition in gastric cancer via the Ras/Raf1/ERK signaling pathway

Abstract

Gastric cancer (GC) is one of the most common malignancies worldwide. TGF-β1 induces the epithelial-mesenchymal transition (EMT) in GC, mainly through Smad-dependent pathways. Nevertheless, few studies have focused on the activation of non-canonical transduction pathways. TRPC, Ca entry channels, are ubiquitously expressed in various cell types and are involved in many cellular functions. However, their roles in GC are not well elucidated. This study aimed to determine whether TRPC participates in the TGF-β1-induced EMT of GC and to investigate the potential mechanisms. Immunofluorescence staining was performed to examine the distribution and expression of TRPCs and EMT-related proteins in SGC-7901 cells incubated with or without TGF-β1. The expression of TRPC1/3/6 and EMT-related molecules, including E-cadherin, vimentin, and α-SMA, was detected by qRT-PCR and Western blotting. Additionally, the underlying mechanism was determined by treating cells with pharmacological inhibitors and examining the levels of proteins involved in the main signaling cascades using Western blotting. TRPC1/3/6 were expressed at high levels in SGC-7901 cells. Following TGF-β1 stimulation, the expression of vimentin, α-SMA, and TRPC1/3/6 increased and E-cadherin expression decreased, accompanied by activation of the Ras/Raf1/ERK1/2 signaling pathway. Notably, activation of the Ras/Raf1/ERK1/2 signaling cascade was suppressed by SKF96365 and 2-APB. Both TRPC and ERK inhibitors mitigated EMT progression. Based on these results, TRPC1/3/6 inhibition attenuated the TGF-β1-induced EMT in GC by suppressing Ras/Raf1/ERK signal transduction.

Aberrant Methylation and Differential Expression of SLC2A1, TNS4, GAPDH, ATP8A2, and CASZ1 Are Associated with the Prognosis of Lung Adenocarcinoma

“…Cell adhesion molecules are closely related to the invasion and migration of multiple tumors [ 33 – 35 ]. The Ras gene is abnormally expressed in gastric cancer [ 36 ], prostate cancer [ 37 ], and colorectal cancer [ 38 ], and it is associated with epithelial-mesenchymal transition (EMT) and drug resistance of cancer. These evidences suggest that the DGs Hyper and the UGs Hypo may play an important regulatory role in the molecular mechanism of LUAD.…”

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

“…These Ca 2+ -permeable nonselective cation channels likely participate in tumor development to different extents by affecting cell metabolism, controlling cell proliferation, promoting angiogenesis, and supporting cell migration and invasion during tumor progression. One of the common effects that had been frequently seen for TRPC channels is the role on epithelial mesenchymal transition (EMT) (Ge et al, 2018;Xu et al, 2018;Xu, Liu, Li, Ma, & Zhang, 2017), but the underlying mechanism remains to be elucidated. In addition, as described earlier, TRPC5 has been implicated in chemoresistance (Ma et al, 2012; Although much evidence about the involvement of individual TRPC subtypes in various cancers have been obtained by the examination of mRNA and protein expression and gene silencing with siRNA, pharmacological evidence is also accumulating.…”

RNA-seq analysis reveals TRPC genes to impact an unexpected number of metabolic and regulatory pathways

“…TRPC1 is also involved in the inflammatory response to bacterial infection through the TLR4/TRPC1/NF-kB signaling route 95 . In addition, TRPC1 appears to contribute to the regulation of the epithelial-mesenchymal transition (EMT) in cancer; its inhibition suppresses TGF-β1-induced EMT 96,97 . TRPC3 is expressed in various immune cells and has been proposed to contribute to vascular inflammation [98][99][100] .…”