Loss of MIR503HG facilitates papillary renal cell carcinoma associated lymphatic metastasis by triggering NOTCH1/VEGFC signaling

Clinical lymphatic metastasis indicates an extremely poor prognosis. Patients with papillary renal cell carcinoma (pRCC) have a high probability of progressing to lymphatic metastasis. However, the molecular mechanism of pRCC-associated lymphatic metastasis has not been elucidated. In this study, we found a downregulated long non-coding RNA (lncRNA) MIR503HG in pRCC primary tumor tissues due to hypermethylation at the CpG islands within its transcriptional start site. Decreased MIR503HG expression could stimulate tube formation and migration of human lymphatic endothelial cell (HLEC) and play a central role to promote lymphatic metastasis in vivo by enhancing tumor lymphangiogenesis. MIR503HG, located in the nucleus, bound with histone variant H2A.Z and affected the recruitment of histone variant H2A.Z to chromatin. Subsequently, increasing the H3K27 trimethylation caused by MIR503HG-overexpression epigenetically downregulated the NOTCH1 expression, which ultimately resulted in decreasing VEGFC secretion and lymphangiogenesis. Additionally, downregulated MIR503HG facilitated the HNRNPC expression, which ultimately promoted the maturation of NOTCH1 mRNA. Notably, upregulating MIR503HG expression might decrease pRCC resistance to the mTOR inhibitor. Together, these findings highlighted a VEGFC-independent mechanism of MIR503HG-mediated lymphatic metastasis. MIR503HG, identified as a novel pRCC-suppressor, would serve as the potentially biomarker for lymphatic metastasis.