Increasing HER2 α2,6 sialylation facilitates gastric cancer progression and resistance via the Akt and ERK pathways

Liu,Naihua; Zhu,Menglu; Linhai,Yingjie; Song,Yuwei; Gui,Xiujuan; Tan,Guoqiang; Li,Jinyuan; Liu,Yan; Deng,Zhendong; Chen,Xiaoting; Wang,Jing; Jia,Lili; He,Xiuzhen; Wang,Xiaoyu; Lin,Shaoqiang

doi:10.3892/or.2018.6680

Increasing HER2 α2,6 sialylation facilitates gastric cancer progression and resistance via the Akt and ERK pathways

Authors:
- Naihua Liu
- Menglu Zhu
- Yingjie Linhai
- Yuwei Song
- Xiujuan Gui
- Guoqiang Tan
- Jinyuan Li
- Yan Liu
- Zhendong Deng
- Xiaoting Chen
- Jing Wang
- Lili Jia
- Xiuzhen He
- Xiaoyu Wang
- Shaoqiang Lin
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Affiliations: Clinical Department of Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080, P.R. China, School of Pharmaceutical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China, Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
Published online on: August 31, 2018 https://doi.org/10.3892/or.2018.6680
Pages: 2997-3005

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Abstract

Upregulated β-galactoside α2,6-sialyltransferase I (ST6Gal-I) expression reportedly occurs in many cancers and is correlated with metastasis and poor prognosis. However, the mechanisms by which ST6Gal‑I facilitates gastric cancer progression remain poorly understood. Trastuzumab is exclusively used in human epidermal growth factor receptor 2 (HER2)+ gastric cancers; however, most advanced HER2+ gastric cancers develop trastuzumab resistance. Herein, we identified HER2 as an ST6Gal‑I substrate and showed that HER2 α2,6 sialylation confers protection against trastuzumab‑mediated apoptosis. SGC7901 cancer cell models in which ST6Gal‑I was overexpressed or knocked down were constructed, revealing that ST6Gal‑I overexpression induced high HER2 sialylation levels and increased cell viability and invasion compared to those in the vector cell line under serum starvation; ST6Gal‑I knockdown had the opposite effects. ST6Gal‑I overexpression also potentiated cell cycle arrest in the G2/S phase to reduce drug sensitivity. In addition, FACS analysis revealed that high ST6Gal‑I levels increased resistance to trastuzumab‑induced apoptosis, accompanied by decreased caspase‑3 levels. However, the ST6Gal‑I knockdown cell line revealed increased caspase‑3 levels and evident apoptosis compared with those in the vector cell line. Although ST6Gal‑I overexpression increased HER2 sialylation, corresponding to decreased HER2 phosphorylation, high α2,6‑sialylation enhanced Akt and ERK phosphorylation levels compared to those in the vector cell line; ST6Gal‑I knockdown had the opposite effects. Collectively, these results implicated a functional role of ST6Gal‑I in promoting tumor cell progression and trastuzumab resistance.

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