TRPC7 facilitates cell growth and migration by regulating intracellular Ca2+ mobilization in lung adenocarcinoma cells

Abstract

Transient receptor potential canonical 7 (TRPC7) has been reported to mediate aging-associated tumorigenesis, but the role of TRPC7 in cancer malignancy is still unclear. TRPC7 is associated with tumor size in patients with lung adenocarcinoma and the present study further evaluated the underlying mechanism of TRPC7 in the regulation of cancer progression. The clinicopathological role of TRPC7 was assessed using immunohistochemistry staining and the pathological mechanism of TRPC7 in lung adenocarcinoma cells was determined using cell cycle examination, invasion and calcium response assays, and immunoblot analysis. The results indicated that high TRPC7 expression was associated with a lower 5-year survival rate compared with low TRPC7 expression, which suggested that TRPC7 expression was inversely associated with overall survival in patients with lung adenocarcinoma. TRPC7 serves a pathological role by facilitating the enhancement of cell growth and migration with increased phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II, AKT and ERK. TRPC7 knockdown in lung adenocarcinoma cells restrained cell cycle progression and cell migration by interrupting the TRPC7-mediated Ca 2+ signaling-dependent AKT and MAPK signaling pathways. These findings demonstrated for the first time a role of oncogenic TRPC7 in the regulation of cancer malignancy and could provide a novel therapeutic molecular target for patients with lung adenocarcinoma.

Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

“…TRP has 28 different families divided into six subfamilies encoded by TRP genes such as TRPC (canonical), TRPV (vanilloids), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystins), and TRPML (mucolipins) [ 27 , 28 ] . TRPC7 enhances cell growth and migration with the activation of Ca 2+ /CaM-dependent protein kinase II (CAMKII), phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular signal-regulated kinase (ERK) [ 29 ] . Three isoforms of NCX are found in cells: NCX1-3 [ 30 ] .…”

“…These factors promote cancer growth by inducing the expression of G1 and G1/S phase transition cyclins and associated cyclin-dependent kinases (CDK4 and CDK2) [ 12 , 13 ] . Ca 2+ is also involved in pathways such as mitogen-activated protein kinases (MAPK) and PI3K/Akt that promote malignancy in cancer cells [ 29 ] .…”

“…Dysregulation of various channels, pumps, transporters, and proteins occurs in different cancer types, leading to either upregulation or downregulation depending on their survival benefits [ 42 , 55 ] . For instance, in a clinical study on lung adenocarcinoma, TRPC7 expression varied among patients [ 29 ] . Consequently, studies have explored the modulation of Ca 2+ levels as a therapeutic target.…”

“…Similarly, TRPM2 expression negatively correlates with prognosis in hepatocellular carcinoma patients [ 61 ] . In lung adenocarcinoma patients, overexpression of TRPC7 is associated with poor prognosis and lower survival rates [ 29 ] . The study by Wang et al has shown that overexpression of PMCA4 is associated with good prognosis in gastric cancer patients [ 62 ] .…”

“…TRPC7 has been implicated in mediating CaMKII, Akt, and MAPK signalling, which are crucial in cancer progression. Knockdown or inhibition of TRPC7 has been shown to suppress the activation of CaMKII, Akt, and ERK [ 29 ] .…”