Modification of α2,6-sialylation mediates the invasiveness and tumorigenicity of non-small cell lung cancer cells in vitro and in vivo via Notch1/Hes1/MMPs pathway

The alterations of sialylation on cell surface N-glycans due to overexpression of different sialyltransferases play a vital role in tumorigenesis and tumor progression. The beta-galactoside alpha 2-6-sialyltransferase 1 (ST6Gal-I) has been reported to be highly expressed in several cancers, including breast cancer, hepatocellular cancer and colon carcinoma. However, the roles and underlying mechanisms of ST6Gal-I in non-small cell lung cancer (NSCLC) still need to be elucidated. In this study, we determined that mRNA levels of ST3GAL1, ST6GALNAC3 and ST8SIA6 were remarkably reduced in lung cancer tissues and cells, whereas ST6GAL1 level significantly increased. The mRNA, protein and glycan levels of ST6Gal-I were higher in lung cancer tissues and cells. Moreover, down-regulation of ST6Gal-I decreased protein levels of Jagged1, DLL-1, Notch1, Hes1, Hey1, matrix-metalloproteinases (MMPs) and VEGF, and suppressed proliferation, migration and invasion capabilities of A549 and H1299 cells in vitro. In vivo, ST6Gal-I silencing suppressed tumorigenicity of NSCLC cells in athymic nude mice via the Notch1/Hes1/MMPs pathway. In addition, overexpression of Notch1 rescued the reduced growth and metastasis of A549 and H1299 cells resulted by ST6Gal-I silencing. Modification of alpha 2,6-sialylation positively associates with lung cancer progression, thereby indicating that ST6Gal-I may mediate the invasiveness and tumorigenicity of NSCLC cells via the Notch1/Hes1/MMPs pathway both in vitro and in vivo. Thus, our results provide a novel therapeutic approach for blocking metastasis in lung cancer patients.