Collagen XV mediated the epithelial-mesenchymal transition to inhibit hepatocellular carcinoma metastasis.

Abstract

Hepatocellular carcinoma (HCC) is a malignant cancer with rapid progression, vascular invasion, a high recurrence rate and poor prognosis, so it is necessary to take early measures to halt this process. Accumulating evidence indicates that collagen XV (translated by Col15a1) is a basement membrane molecule related to tumour metastasis in several organs. However, the potential function of collagen XV in the liver associated with HCC remains to be further elucidated. Col15a1 was overexpressed in HepG2 and HCCLM3 cells. CCK8 and colony formation assays were used to assess the capacity of cell proliferation, and Transwell and wound healing assays were utilized to measure cell migration. Western blotting and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) quantified the protein and mRNA expression levels of genes related to the epithelial-mesenchymal transition (EMT). Then, the effect of collagen XV on tumour metastasis was confirmed in vivo. Finally, we inhibited discoidin domain receptor 1 (DDR1) via DDR1-IN-1 to explore whether the collagen XV interacted with DDR1 to regulate EMT. Patients of HCC with higher expression of Col15a1 showed better survival than patients with low expression. Overexpression of collagen XV in HepG2 and HCCLM3 cells suppressed cell proliferation and migration in vitro and inhibited pulmonary and liver metastasis in vivo. In addition, collagen XV downregulated the DDR1 and transcription factor (Snail, Slug), regulated the EMT markers (Vimentin, E-cadherin, N-cadherin, and MMP9). Furthermore, inhibition of the DDR1 receptor by DDR1-IN-1 suppressed the gene promoting the EMT. Collagen XV functioned as a metastasis inhibitor in HCC by regulating the DDR1-Snail/Slug axis to regulate EMT.