Abstract
Background Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.
Highlights
Colon cancer is one of the most prevalent malignancies globally and has consistently ranked in the top three leading causes of cancer-associated death [1]
Because advanced colorectal cancer can be defined as colorectal cancer that metastasizes when it appears or recurs, we analyzed the difference in plasmacytoma variant translocation 1 (PVT1) expression between primary and metastatic tumors from the GSE49355 dataset
These results suggest a relationship between the exosomal long ncRNA (lncRNA) PVT1/vascular endothelial growth factor A (VEGFA) axis and metastatic colorectal cancer
Summary
Colon cancer is one of the most prevalent malignancies globally and has consistently ranked in the top three leading causes of cancer-associated death [1]. A recent study revealed that colon cancer cells secrete exosomes containing an ncRNA, namely, miR-193a, which interacts with major vault protein to promote cancer progression [7]. These exosomes can be detected in serum, making them ideal prognostic markers. The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR) This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker
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