Tn antigen promotes human colorectal cancer metastasis via H‐Ras mediated epithelial‐mesenchymal transition activation

Abstract

Tn antigen is a truncated O‐glycan, frequently detected in colorectal cancer ( CRC ), but its precise role in CRC metastasis is not well addressed. Here we investigated the effects of Core 1 β3Gal‐T specific molecular chaperone (Cosmc) deletion‐mediated Tn antigen exposure on CRC metastasis and its underlying mechanism. We first used CRISPR /Cas9 technology to knockout Cosmc, which is required for normal O‐glycosylation, and thereby obtained Tn‐positive CRC cells. We then investigated the biological consequences of Tn antigen expression in CRC . The results showed that Tn‐positive cells exhibited an enhanced metastatic capability both in vitro and in vivo. A further analysis indicated that Tn antigen expression induced typical activation of epithelial‐mesenchymal transition ( EMT ). Mechanistically, we found that H‐Ras, which is known to drive EMT , was markedly up‐regulated in Tn‐positive cells, whereas knockdown of H‐Ras suppressed Tn antigen induced activation of EMT . Furthermore, we confirmed that LS 174T cells (Tn‐positive) transfected with wild‐type Cosmc, thus expressing no Tn antigen, had down‐regulation of H‐Ras expression and subsequent inhibition of EMT process. In addition, analysis of 438 samples in TCGA cohort demonstrated that Cosmc expression was reversely correlated with H‐Ras, underscoring the significance of Tn antigen‐H‐Ras signalling in CRC patients. These data demonstrated that Cosmc deletion‐mediated Tn antigen exposure promotes CRC metastasis, which is possibly mediated by H‐Ras‐induced EMT activation.

Fusobacterium nucleatum Promotes Metastasis in Colorectal Cancer by Activating Autophagy Signaling via the Upregulation of CARD3 Expression

“…Most patients with CRC die from metastasis 41,42. Thus, understanding the mechanisms of metastasis in CRC is essential for optimizing current therapeutic strategies.…”

Tn Antigen Expression Contributes to an Immune Suppressive Microenvironment and Drives Tumor Growth in Colorectal Cancer

“…In literature, conflicting reports exist on the influence of Tn or T antigen on tumor development. Overexpression of Tn antigen has been shown to promote tumor growth in CRC (11,51) and pancreatic cancer (13). Moreover, in some models the mere abrogation of T-synthase/COSMC is sufficient to induce oncogenic features and to augment tumorigenesis of otherwise healthy cells (12,52).…”

Altered Glycosylation Contributes to Placental Dysfunction Upon Early Disruption of the NK Cell-DC Dynamics

“…Both depletion of NK cells or expansion of DC in absence of dangers signals increased Tn antigen expression in the decidua. Since Tn antigen expression has been linked to enhanced growth and invasion ability in cancer cells ( 33 – 35 ), it is possible that increased decidual Tn antigen expression would act to facilitate trophoblast invasion. In this regard, trophoblast giant cells showed intense staining with LEA, indicating increased expression of LacNAc core 2 O-glycans during normal pregnancy.…”