N‐acetylglucosaminyltransferase V modulates radiosensitivity and migration of small cell lung cancer through epithelial–mesenchymal transition

Abstract

N-acetylglucosaminyltransferase V (Gnt-V) has been linked to the migration of various human cancers. Recently we have found that inhibition of Gnt-V increases the radiosensitivity of cancer cells. However, the mechanisms by which Gnt-V mediates radiosensitivity and migration, especially in small cell lung cancer (SCLC) remain unknown. In our study, two SCLC cell lines (H1688 and H146) were used to investigate whether Gnt-V modulated the radiosensitivity and migration of SCLC cells through the epithelial-mesenchymal transition (EMT). The results showed that the expression of Gnt-V correlated with the N stage in patients with SCLC. Overexpression of Gnt-V led to a further increase in the relative viable cell number and survival fraction with a decrease in apoptosis rate and Bax/ Bcl-2 ratio, when the cells were treated with irradiation. By contrast, knockdown of Gnt-V with irradiation resulted in a further decrease in the relative viable cell number and survival fraction but an increase in apoptosis rate and Bax/Bcl-2 ratio. Cells expressing high levels of Gnt-V increased migration whereas low levels of Gnt-V suppressed cell migration. Besides, the transient knockdown of ZEB2 led to an increase in radiosensitivity and an inhibition in the migration of SCLC cells. Furthermore, Gnt-V was negatively correlated with E-cadherin expression but positively correlated with N-cadherin, vimentin and ZEB2 expression. Finally, an in vivo study revealed that upregulation of Gnt-V caused tumour growth more quickly, as well as the expression of EMT-related markers (N-cadherin, vimentin and ZEB2). Taken together, the study suggested that an elevation of Gnt-V could lead to the radiosensitivity and migration of SCLC cells by inducing EMT, thereby highlighting Gnt-V as a potential therapeutic target for the prevention of EMT-associated tumour radioresistance and migration.

Plasma N-glycans in colorectal cancer risk

“…This glycan is highly branched and requires activity of the GNT-V protein, which is a product of the MGAT5 gene. This gene has been implicated in ulcerative colitis 40 , gastric 41 and small cell lung cancer 42 . To the best of our knowledge, this is the first report of a specific glycan level being associated with colorectal cancer family history.…”

Conditioned Medium from Malignant Breast Cancer Cells Induces an EMT-Like Phenotype and an Altered N-Glycan Profile in Normal Epithelial MCF10A Cells

“…An increased expression of sialic acids, which attach to the terminal of N -glycans and influence cell adhesion, has been considered as an important modification of many carcinomas [ 25 ]. The bisected GlcNAc structure formed by N -acetylglucosaminyltransferase III (GnT-III) has been reported to be downregulated during a TGF-β-induced EMT process [ 26 ], whereas the β1-6 branching of N -glycan structures catalyzed by N -acetylglucosaminyltransferase V (GnT-V) are increased in malignant cancers and EMT transition [ 27 , 28 ]. Altered glycan profiles were detected in hepatocellular carcinoma HUH7 cells during hepatocyte growth factor (HGF)-induced EMT by a lectin microarray [ 5 ].…”

N‐acetylglucosaminyltransferase‐I as a novel regulator of epithelial‐mesenchymal transition

“…In contrast to TGF-bmediated signaling, a1,6-fucosylation on an activin receptor, a member of the TGF-b superfamily, negatively regulates phospho-Smad-2 signaling (68). In addition, cells expressing high levels of GnT-V increase migration (69) and EMT behavior by up-regulating EGFR signaling (64). However, lower expression of GnT-V is found in lung cancer, and GnT-V inversely regulates EMT behavior by suppressing Smad activation in human lung cancer cells (70).…”