Gastric Cancer Cell Glycosylation as a Modulator of the ErbB2 Oncogenic Receptor

Abstract

Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2) constitute crucial molecular events underpinning gastric neoplastic transformation. Despite ErbB2 extracellular domain being a well-known target for glycosylation, its glycosylation profile and the molecular mechanisms through which it actively tunes tumorigenesis in gastric cancer (GC) cells remain elusive. We aimed at disclosing relevant ErbB2 glycan signatures and their functional impact on receptor’s biology in GC cells. The transcriptomic profile of cancer-relevant glycosylation enzymes, and the expression and activation of the ErbB receptors were characterized in four GC cell lines. Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harboring the tumor-associated sialyl Lewis a (SLea) antigen. The expression of SLea and key enzymes integrating its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of ERBB2 and FUT3, a central gene in SLea biosynthesis, was disclosed in GC patients, further highlighting the crosstalk between ErbB2 and SLea expression. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLea drastically altered ErbB2 expression and activation in NCI-N87 cells. Altogether, NCI-N87 cell line constitutes an appealing in vitro model to address glycan-mediated regulation of ErbB2 in GC.

Study on the mechanisms of compound Kushen injection for the treatment of gastric cancer based on network pharmacology

“…The epidermal growth factor-related protein (ErbB) family of receptor tyrosine kinases plays an important role in epithelial cell development. The overexpression of human epidermal growth factor receptor 2 (ERBB2) promotes the differentiation and proliferation of cancer cells, which is recognized as one of the key causes of GC and seriously affects the prognosis of GC patients [52,53]. At present, there is no in vivo or in vitro experiment to confirm that CKI achieves the therapeutic effect of GC by interfering with ERBB2, which is an important potential direction for future research.…”

Enhancement of Wound Healing by Topical Application of Epidermal Growth Factor in Animal Model

“…In literature reports, another toxicological test was applied 6g (200µg EGF/g) rhEGF gelatin to the skin wound for 36 days on the back of a rabbit, 20 times its clinical dose, no adverse side effects regarding the local skin and organ toxicity was observed (data not shown). Moreover, in vivo over expression of epidermal growth factor in transgenic mice could lead to growth retardation, but no tumor was observed in transgenic animals [42][43][44][45][46][47][48] . In current study realized that in preparation of rhEGF medicine based on the earlier experiments of an oncogenic pml/retinoic acid receptor alpha fusion (retinoid pharmacology) in APL and an aberrant androgen receptor with its methyltestosterone drug in the induction of breast tumors 29,30 and subsequentially the earliest discovery of normal or proto-oncogenic receptor kinase EGF receptor in cell proliferative signaling in wound healing, and in June,1991 patent application for rhEGF powder and its specific Shampo liquid, and its newly Band-Aids.…”

Core 1–derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer

“…Exposure of the immature glycan Tn antigen is observed in biopsies of gastritis and gastric cancer patients independent of H. pylori status (Barresi et al, 2001; Persson et al, 2017). In vitro studies suggest O-glycan truncation itself may lead to cell-intrinsic defects that perturb epithelial homeostasis (Duarte et al, 2017; Radhakrishnan et al, 2014). However, the role of abnormal O-glycosylation in homeostasis of the gastric mucosa in vivo is unknown.…”