ABSTRACT
Cancer-associated fibroblasts (CAFs) play a pivotal role in the development and progression of many human cancers. Recent studies have shown that Hedgehog (Hh) signalling modulates the stromal microenvironment and prepares a suitable niche for tumour metastasis. However, the detailed molecular mechanisms underlying CAF-mediated lymphangiogenesis have not been fully elucidated. Therefore, our goal is to illustrate whether Hh ligands can activate Hh signalling in CAFs in a paracrine fashion and elucidate the effect of CAFs on lymphangiogenesis. We determined here that Sonic Hedgehog (SHH) secreted by ovarian cancer (OC) cells activated Hh signalling in CAFs and promoted the proliferation of CAFs. Moreover, we co-injected SHH-overexpressing OC cells and CAFs in a xenograft model and found that the CAFs accelerated tumourigenesis and lymphangiogenesis in OC. Mechanistically, we found that SHH secreted by the OC cells induced VEGF-C expression in CAFs. Inhibition of Hh signalling in CAFs decreased VEGF-C expression and diminished the positive role of CAFs in supporting tumourigenesis and lymphangiogenesis in a murine xenograft model. Our results demonstrate that CAFs constitute a supportive niche for cancer lymphangiogenesis via the Hh/VEGF-C signalling axis and provide evidence for the clinical application of Hh inhibitors in the treatment of OC.
ABSTRACT
OBJECTIVE: To verify whether miR-218 could inhibit human trophoblastic cell (HTR-8 cells) migration and invasion by target-ing sex determining region Y-box 4(SOX4). METHODS: The serum samples were collected from 46 hypertensive disorder complicating pregnan-cy (HDCP) and 50 normal pregnant women. RT-PCR was used to test the expression of miR-218 in the serum. In vitro, MiR-218 was trans-fe cted into HTR-8 cells. The HTR-8 cells were divided into three groups:normal control group, mimic control and miR-218 mimic group. The migratory and invasion ability of HTR-8 cells was tested, and the expressions of matrix metalloproteinase-2(MMP-2), MMP-9 and Sox4 were also investigated in the cells of each group. Luciferase assay was used to confirme whether Sox4-3'-UTR was the target gene of miR-218. RESULTS: The expression of miR-218 was decreased in the serum of HDCP patients compared with the normal pregnant woman(P < 0.01). In vit-ro, compared with the control group, the invasion and migration ability of HTR-8 cells and the expression of MMP-2 MMP-9 and SOX4 were decreased in the miR-218 group (P < 0.01); The Luciferase activity of the SOX4-3'-UTR plasmid was significantly suppressed by miR-218 (P < 0.01); Over expression of SOX4 could reverse the effect of miR-218 on HTR-8 cells(P < 0.01). CONCLUSIONS: The expression of miR-218 decreases in the serum of HDPC patients and miR-218 inhibits HTR-8 cells invasion by targeting SOX4-3'-UTR.
