Vascular Endothelial Growth Factor Production by Interleukin‐17C‐Stimulated Colorectal Cancer Cells Is Dependent on the STAT3/miR‐23a‐3p Signaling

Abstract

Recent studies have shown that interleukin‐17C (IL‐17C) is associated with tumor initiation and progression of colorectal cancer (CRC). However, the detailed mechanism of action remains to be elucidated. We aimed to investigate the effect of IL‐17C on angiogenesis and delineate the direct target genes of IL‐17C signaling in CRC. Aims were tested by using angiogenesis assays, murine xenograft experiments, immunohistochemical staining, gene silencing, quantitative real time PCR, ELISA, and western blot analysis. IL‐17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD‐1 cells. IL‐17C‐conditioned DLD‐1 cells enhanced angiogenesis by secreting vascular endothelial growth factor (VEGF). Moreover, IL‐17C significantly increased xenograft tumor growth via VEGF production, but treatment with the VEGF receptor 2 inhibitor Ki8751 ameliorated its tumor promoting activity. IL‐17C also increased levels of PECAM and VE‐cadherin in tumor tissues, which was suppressed by Ki8751. Furthermore, IL‐17C increased miR‐23a‐3p expression via STAT3 phosphorylation. Accordingly, miR‐23a‐3p suppressed semaphorin 6D (SEMA6D) expression, enabling VEGF induction. Therefore, our data showed that IL‐17C promotes tumorigenesis and angiogenesis through VEGF production via the STAT3/miR‐23a‐3p/SEMA6D axis, suggesting its potential as a novel target for anti‐CRC therapy.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1A2C1010536 to E.I.).