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Asporin enhances colorectal cancer metastasis through activating the EGFR/src/cortactin signaling pathway.

ABSTRACT: Asporin has been implicated as an oncogene in various types of human cancers; however, the roles of asporin in the development and progression of colorectal cancer (CRC) have not yet been determined. With clinical samples, we found that asporin was highly expressed in CRC tissues compared to adjacent normal tissues and the asporin expression levels were significantly associated with lymph node metastasis status and TNM stage of the patients. Through knockdown of asporin in CRC cell lines RKO and SW620 or overexpression of asporin in cell lines HT-29 and LoVo, we found that asporin could enhance wound healing, migration and invasion abilities of the CRC cells. Further more, with the human umbilical vein endothelial cells (HUVECs) tube formation assays and the xenograft model, we found that asporin promoted the tumor growth through stimulating the VEGF signaling pathway. The portal vein injection models suggested that asporin overexpression stimulated the liver metastasis of HT29 cell line, while asporin knockdown inhibited the liver metastasis of RKO cell line. In addition, asporin was found to augment the phosphorylation of EGFR/src/cortactin signaling pathway, which might be contributed to the biological functions of asporin in CRC metastasis. These results suggested that asporin promoted the tumor growth and metastasis of CRC, and it could be a potential therapeutic target for CRC patients in future.

SUBMITTER: Wu H

PROVIDER: S-EPMC5341987 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThis paper aims to explore the effects of plasminogen activator, urokinase (PLAU) expression on the migration, invasion, and proliferation of colorectal cancer (CRC) cells and to preliminarily analyze its possible mechanism, thereby laying a foundation for the research on potential biological targets of CRC.MethodsCRC-related mRNA was screened in Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/gds/). Differentially expressed genes (DEGs) were obtained for functional enrichment analysis. The enriched pathway and key involved functional gene were screened for further in vitro and in vivo analysis CRC cells were transfected with PLAU-NC (negative control), PLAU-mimic, and PLAU-inhibitor for 48 h and divided into the above groups for later studies. The migration, invasion, and proliferation capacities of CRC cells were detected using wound healing, Transwell, and colony formation assays, respectively. The Src inhibitor saracatinib (AZD0530) was added to the PLAU-NC and PLAU-mimic groups, and the expression levels of Src/extracellular signal-regulated kinase (ERK) pathway-, migration-, invasion-, and proliferation-related proteins were detected by Western blotting.ResultsThe results showed that after upregulation of PLAU, the number of CRC cells (SW480) that migrated to the center of the wound significantly increased, the number of cells that migrated and invaded through the basement membrane increased in the PLAU-mimic group, and the number of colonies also increased. These results suggest that increasing PLAU expression promotes the migration, invasion, and proliferation of CRC cells. At the same time, the molecular mechanism of PLAU in CRC cells was investigated by downregulating the protein expression of Src combined with the results of the bioinformatics analysis. Western blotting revealed that the protein expressions of phosphorylated Src (p-Src) and phosphorylated ERK (p-ERK) in SW480 and SW620 cells increased significantly in the PLAU-mimic group compared with the PLAU-NC group, while the results were the opposite in the PLAU-inhibitor group. After being treated with saracatinib, we observed significantly decreased protein levels of p-ERK, matrix metallopeptidase 2 (MMP-2), MMP-3, MMP-9, Cyclin D1, and Cyclin A2 in the SW480 cells.ConclusionsIn conclusion, PLAU affects the migration, invasion, and proliferation of CRC cells by activating the Src/ERK pathway.

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Asporin enhances colorectal cancer metastasis through activating the EGFR/src/cortactin signaling pathway.

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