Lymphatic metastasis is the leading cause responsible for recurrence and progression in
papillary thyroid cancer (PTC), where dysregulation of long non-coding RNAs (lncRNAs) has been extensively demonstrated to be implicated. However, the specific lymphatic node metastatsis-related lncRNAs remain not identified in PTC yet. Lymphatic node metastatsis-related
lncRNA, MFSD4A-AS1, was explored in the PTC dataset from The
Cancer Genome Atlas and our clinical samples. The roles of MFSD4A-AS1 in
lymphatic metastasis were investigated in vitro and in vivo. Bioinformatic analysis,
luciferase assay and
RNA immunoprecipitation assay were performed to identify the potential targets and the underlying pathway of MFSD4A-AS1 in
lymphatic metastasis of PTC. MFSD4A-AS1 was specifically upregulated in PTC tissues with
lymphatic metastasis. Upregulating MFSD4A-AS1 promoted mesh formation and migration of human umbilical vein endothelial cells and invasion and migration of PTC cells. Importantly and consistently, MFSD4A-AS1 promoted
lymphatic metastasis of PTC cells in vivo by inducing the lymphangiogenic formation and enhancing the invasive capability of PTC cells. Mechanistic dissection further revealed that MFSD4A-AS1 functioned as
competing endogenous RNA to sequester miR-30c-2-3p, miR-145-3p and miR-139-5p to disrupt the
miRNA-mediated inhibition of
vascular endothelial growth factors A and C, and further activated
transforming growth factor (TGF)-β signaling by sponging miR-30c-2-3p that targeted
TGFBR2 and USP15, both of which synergistically promoted lymphangiogenesis and
lymphatic metastasis of PTC. Our results unravel novel dual mechanisms by which MFSD4A-AS1 promotes
lymphatic metastasis of PTC, which will facilitate the development of anti-lymphatic metastatic therapeutic strategy in PTC.