Hedyotis diffusa Willd. inhibits VEGF‑C‑mediated lymphangiogenesis in colorectal cancer via multiple signaling pathways.

Abstract

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. For patients diagnosed with the presence of metastatic disease, surgery is not suitable for the majority of them. Lymphangiogenesis is a key factor during cancer metastasis and is regulated by vascular endothelial growth factor C (VEGF‑C). Hedyotis diffusa Willd. (HDW) is a Chinese herb of the Rubiaceae family that reportedly inhibits tumor metastasis. However, its underlying anticancer mechanisms have not yet been elucidated. In the present study, we investigated the effects of an ethanol extract of HDW (EEHDW) on the migration capacity by wound healing and Transwell assays, and the effect on the VEGF‑C expression in different CRC cell lines by western blot analysis and ELISA assays. A model of VEGF‑C‑stimulated human lymphatic endothelial cells (HLECs) was constructed. It was found that EEHDW suppressed lymphangiogenesis via the mediation of multiple pathways, which attenuated the migration of cells and their tube formation abilities. Multiple signaling pathways were found to be involved in the VEGF‑C‑mediated lymphangiogenesis. After EEHDW treatment in VEGF‑C‑stimulated HLECs, EEHDW was found to downregulate the expression levels of multiple signaling pathways. Taken together, these results indicate that EEHDW possesses significant anti‑metastatic activities. Moreover, the suppressive effect of EEHDW on lymphangiogenesis, particularly via downregulation of VEGF‑C, partly explains the potential molecular mechanism underlying the inhibitory effect of EEHDW on CRC metastasis.