MiRNA-155 regulates lymphangiogenesis in natural killer/T-cell lymphoma by targeting BRG1

Abstract

Background: miR-155 was up-regulated in natural killer/T-cell lymphoma (NKTCL), an aggressive malignancy, and correlated with disease progression. However, minimal is known on biological activities and underlying mechanisms of miR-155 in NKTCL. In this study, we examined BRG1, a potential target of miR-155, and focused on the miR-155/BRG1 signaling in regulating lymphangiogenesis of NKTCL. Methods: The expression of miR-155, BRG1, VEGFC, and VEGFD was compared between two NKTCL cell lines and normal NK cells. The critical role of miR-155 and STAT3 was assessed using miR-155 inhibitor and STAT3 inhibitor S31-201, respectively. Two biological phenotypes, apoptosis and pro-lymphangiogenesis, were examined in vitro by flow cytometry and lymphatic tube formation, respectively, and in vivo using an NKTCL xenograft model. Results: The miR-155 level negatively correlated with BRG1, but positively with VEGFC in normal NK as well as two NKTCL cell lines. Targeting miR-155 in NKTCL cells significantly boosted BRG1 expression and decreased the activated STAT3 or VEGFC level, leading to enhanced apoptosis and reduced lymphangiogenesis. STAT3 acted downstream of BRG1 and essentially regulated miR-155-mediated up-regulation of VEGFC and pro-lymphangiogenesis. In vivo, targeting miR-155 inhibited primary xenograft growth as well as tumor-associated lymphangiogenesis. Conclusions: By inhibiting BRG1 expression, miR-155 activated STAT3/VEGFC signaling and promoted lymphangiogenesis. In addition, miR-155 also controlled the viability of NKTCL cells. Therefore, targeting miR-155 provides a novel therapy for NKTCL.