Mesenchymal Stem Cells Derived from Adipose Accelerate the Progression of Colon Cancer by Inducing a MT-CAFs Phenotype via TRPC3/NF-KB Axis

Abstract Background: There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. Methods: Gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). We screened out the ion channel protein TRPC3 with WB detecion and lentivirus knockdown. Calcium influx was detected by two-photon microscope. MTS and Transwell detected growth, migration, and invasion of MT-CAFs and HCT116 cells. Bioinformatic tools and clinical specimens were to assess the relationship between TRPC3 and surrvival.Results: We screened out the ion channel protein TRPC3 with significantly increased expression, which caused calcium influx, and further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissue compared with normal colon tissues, and is positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha (FAP). The disease-free survival of patients with positive TRPC3 expression in mesenchymal cells was significantly shorter than in those with negative expression. Conclusions: These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.