Among the various posttranslational modification reactions, glycosylation is the most common, and nearly 50% of all known proteins are thought to be glycosylated. In fact, changes in glycosylation readily occur in carcinogenesis, invasion and metastasis. This report investigated the modification of glycosylation mediated the invasive properties of Hca-F and Hca-P murine hepatocarcinoma cell lines, which have high, low metastatic potential in the lymph nodes, respectively. Analysis revealed that the N-glycan composition profiling, expression of glycogenes and lectin binding profiling were different in Hca-F cells, as compared to those in Hca-P cells. Further analysis of the N-glycan regulation by tunicamycin (TM) application or PNGase F treatment in Hca-F cells showed partial inhibition of N-glycan glycosylation and decreased invasion both in vitro and in vivo. We targeted glycogene ST6GAL1, which was expressed differently in Hca-F and Hca-P cells, and regulated the expression of ST6GAL1. The altered levels of ST6GAL1 were also responsible for changed invasive properties of Hca-F and Hca-P cells both in vitro and in vivo. These findings indicate a role for glycosylation modification as a mediator of tumor lymphatic metastasis, with its altered expression causing an invasive ability differentially.
Dysregulation of Axl receptor tyrosine kinases is implicated in the pathogenesis of several sensitive and refractory cancers. In this study we showed that Axl expression was upregulated in drug-resistant cancer cells, as compared to those in parental cells. Downregulation of Axl expression by RNAi led to a decrease of K562/ADR and MCF-7/ADR cells invasion, proliferation in soft agar, and increased cells chemosensitivity in vitro. In nude mice bearing xenografts, downregulation of Axl in MDR cells enhanced the anticancer activity of intraperitoneally applied chemotherapeutic drugs. Our observations suggest that Axl represents a promising gene for overcoming MDR in cancer therapy.
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