Long noncoding RNA VESTAR regulates lymphangiogenesis and lymph node metastasis of esophageal squamous cell carcinoma by enhancing VEGF-C mRNA stability.

Lymph node (LN) metastasis is one of the most malignant clinical features in patients with esophageal squamous cell carcinoma (ESCC). Understanding the mechanism of LN metastasis will provide treatment strategies for ESCC patients. Long noncoding RNAs (lncRNA) play a critical role in the development and progression of human cancers. However, the role and mechanism of lncRNAs in LN metastasis remain largely unknown. Here we show that VEGF-C mRNA stability-associated long noncoding RNA (VESTAR) is involved in LN metastasis of ESCC. VESTAR was overexpressed in ESCC tissues and was predictive of poor prognosis in patients with ESCC. In ESCC, NXF1 and SRSF3 facilitated nuclear export of VESTAR to the cytoplasm, which was associated with LN metastasis. Depletion of VESTAR inhibited ESCC-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, VESTAR directly bound and stabilized VEGF-C mRNA. VESTAR also interacted with HuR, a positive regulator of VEGF-C mRNA stability, and increased HuR binding to VEGF-C mRNA. Our study reveals a novel lncRNA-guided mechanism of LN metastasis in ESCC and may provide a potential target for treatment of ESCC lymphatic metastasis.