TRPC1 Inhibits Cell Proliferation/Invasion and Is Predictive of a Better Prognosis of Esophageal Squamous Cell Carcinoma

Abstract

Background and ObjectivesIn China, over 90% of esophageal cancer (EC) cases are esophageal squamous cell carcinoma (ESCC). ESCC is a frequently malignant tumor with poor prognosis despite the development of comprehensive therapeutic strategies, for which there is still a lack of effective prognostic factors. Previous studies found that the abnormal expression of TRPC1 is closely related to the proliferation, invasion, metastasis, and differentiation of various tumors. However, the relationship between TRPC1 and ESCC is currently unclear. The present study aimed to clarify the clinical significance of TRPC1 and to preliminarily assess the molecular mechanism by which TRPC1 regulates cell proliferation, migration, and invasion in ESCC.Materials and MethodsImmunohistochemistry (IHC) was used to determine the expression of TRPC1 and Ki-67 in 165 cases of ESCC. The correlations between TRPC1 expression and clinicopathological characteristics were determined, and both univariate and multivariate analyses were utilized to quantify the impact of TRPC1 expression on patient survival. Cell Counting Kit-8, scratch wound healing, and transwell assays were used to determine the effects of TRPC1 on proliferation, migration, and invasion in ESCC in vitro, respectively.ResultsThe positive expression rate of TRPC1 showed significantly decreased in ESCC (45.50%) compared with the levels in normal esophageal mucosa (NEM; 80.80%) and high-grade intraepithelial neoplasia (HGIEN; 63.20%) (P<0.001). Higher expression rate of TRPC1 was associated with low lymph node metastasis (P<0.001), high differentiation (rs= 0.232, P=0.003), and low Ki-67 (rs = −0.492, P<0.001). We further revealed that low expression of TRPC1 was associated with poor prognosis (Disease-free survival, DFS: 95% CI=0.545–0.845, P=0.001; Overall survival, OS: 95% CI=0.553–0.891, P=0.004). Furthermore, we showed that downregulation of TRPC1 promoted the proliferation, migration, and invasion of human esophageal squamous cell carcinoma cell line EC9706 in vitro. In contrast, overexpression of TRPC1 inhibited the proliferation, migration, and invasion of human esophageal squamous cell carcinoma cell line KYSE150 (P<0.01), in a manner at least in part mediated through the AKT/p27 pathway.ConclusionTRPC1 inhibited the proliferation, migration, and invasion of EC9706 and KYSE150 cells, at least, in part mediated through the AKT/p27 pathway in vitro. The downregulation of TRPC1 may be one of the most important molecular events in the malignant progression of ESCC. TRPC1 could be a new candidate tumor suppressor gene and a new prognostic factor of ESCC.

The TRPC1 Channel Forms a PI3K/CaM Complex and Regulates Pancreatic Ductal Adenocarcinoma Cell Proliferation in a Ca2+-Independent Manner

“…Thus, in the lung (A549) and hepatocellular (Huh7) cancer cell lines, the depletion of TRPC1 inhibits cell proliferation by decreasing the activation of AKT [ 28 , 29 ]. Meanwhile, TRPC1 downregulation enhances cell proliferation by activating AKT in the esophageal (EC9706 cells) and breast (MCF-7 cells) carcinoma cell lines [ 32 ]. Recently, it has been shown that TRPC1 interacts with PI3K through calmodulin (CaM).…”

“…In a majority of studies, TRPC1 downregulation inhibits the proliferative rate in neuroblastoma [22], glioblastoma [23], thyroid [24], breast [12,[25][26][27], lung, [28], liver [29,30], ovarian [31], and colon cancer [13]. Whereas in other studies, TRPC1 downregulation drives proliferation and growth in esophageal [32] and breast cancer [33]. Additionally, it is controversial whether the influx of Ca 2+ causes this proliferation through TRPC1.…”

In Silico Analysis of Ion Channels and Their Correlation with Epithelial to Mesenchymal Transition in Breast Cancer

“…Of those, GJA1, AQP1, SCN4B and AQP7 were stated previously in breast cancer tumor growth [41][42][43][44]. Similarly, PKD2, GJA4, KCNJ8, TRPC1, KCNJ2, KCND2, KCNB1, CLIC5, CLIC2 and GABRE were previously reported to have a role in tumor growth in several tumors [45][46][47][48][49][50][51][52][53][54][55][56]. HTR3C, CLCN6, GLRB, SCN3A, ANO3, ANO5, ANO6 and LRRC8C were identified in this study as putative ion channels that may be implicated in tumor growth and development in breast cancer.…”

A TRP Family Based Signature for Prognosis Prediction in Head and Neck Squamous Cell Carcinoma

“…Among them, TRPC1 is known for its role in Ca 2+ influx, cell growth, and migration [ 31 , 32 ]. In esophageal carcinoma, silencing TRPC1 could repress cell viability and metastasis, indicating that TRPC1 is a protective factor in esophageal cancer [ 33 ]. In particular, Osawa et al once reported that TRPC1 is involved in PI3K activation and could enhance Ca 2+ concentration, subsequently promoting ERK phosphorylation and cell migration of HSC-3 [ 34 ].…”