Abstract
Transient receptor potential canonical (TRPC) channels are the most prominent nonselective cation channels involved in various diseases. However, the function, clinical significance, and molecular mechanism of TRPCs in colorectal cancer (CRC) progression remain unclear. In this study, we identified that TRPC1 was the major variant gene of the TRPC family in CRC patients. TRPC1 was upregulated in CRC tissues compared with adjacent normal tissues and high expression of TRPC1 was associated with more aggressive tumor progression and poor overall survival. TRPC1 knockdown inhibited cell proliferation, cell-cycle progression, invasion, and migration in vitro, as well as tumor growth in vivo; whereas TRPC1 overexpression promoted colorectal tumor growth and metastasis in vitro and in vivo. In addition, colorectal tumorigenesis was significantly attenuated in Trpc1-/- mice. Mechanistically, TRPC1 could enhance the interaction between calmodulin (CaM) and the PI3K p85 subunit by directly binding to CaM, which further activated the PI3K/AKT and its downstream signaling molecules implicated in cell cycle progression and epithelial-mesenchymal transition. Silencing of CaM attenuated the oncogenic effects of TRPC1. Taken together, these results provide evidence that TRPC1 plays a pivotal oncogenic role in colorectal tumorigenesis and tumor progression by activating CaM-mediated PI3K/AKT signaling axis. Targeting TRPC1 represents a novel and specific approach for CRC treatment.
Highlights
Colorectal cancer is one of the most common malignant tumors in the world [1]
TRPC1 upregulation is correlated with tumor progression and poor prognosis of colorectal cancer (CRC) patients To identify the correlation between Transient receptor potential canonical (TRPC) and CRC, gene expression data were analyzed in the GENT2 database
The results showed that TRPC1 mRNA expression was significantly higher in Oncogenesis (2021)10:67
Summary
Colorectal cancer is one of the most common malignant tumors in the world [1]. The molecular mechanisms in colorectal cancer initiation and progression are complex and heterogeneous, involving chromosomal instability, microsatellite instability, and abnormal gene amplification, deletion or expression [3,4,5]. Alteration of multiple genes, such as oncogene or tumor suppressor gene, leading to disordered signal transduction, is one of the major mechanisms in colorectal cancer. Despite the high prevalence of gene expression change, their role in the pathogenesis of colorectal cancer remains poorly understood [6]. Identification of novel driver genes may uncover oncogenic pathways underlying the initiation and progression of colorectal cancer and discover potential targets for CRC treatment
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