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

Liu, Naihua; Zhu, Mingjian; Linhai, Yingjie; Song, Yuwei; Gui, Xiujuan; Tan, Guoqiang; Li, Jinyuan; Liu, Yan; Deng, Zhendong; Rothenberg, Marc E.; Wang, Jing; Jia, Lili; He, Xiuzhen; Wang, Xiaoyu; Lin, Shaoqiang

doi:10.3892/or.2018.6680

Cited by 30 publications

(46 citation statements)

References 41 publications

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“…α2,6-sialylation in hepatocellular carcinoma activated Wnt/β-catenin signaling to promote tumor cell proliferation, migration, and invasion [62]. Increased α2,6-sialylation on the human epidermal growth factor receptor 2 (HER2) facilitated gastric cancer progression via the Akt and ERK pathways [63]. Sialylation on the endothelial growth factors receptor (EGFR) was regulated by ST6GAL1 via the PI3K/Akt pathway [64], and inhibition of ST6GAL1 induced EGFR desialylation and anti-proliferation [65].…”

Section: Sialic Acids Enhance Tumor Proliferation and Metastasismentioning

confidence: 99%

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Zhou

Yang

Guan

2020

Cells

132

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Sialic acids, a subset of nine carbon acidic sugars, often exist as the terminal sugars of glycans on either glycoproteins or glycolipids on the cell surface. Sialic acids play important roles in many physiological and pathological processes via carbohydrate-protein interactions, including cell–cell communication, bacterial and viral infections. In particular, hypersialylation in tumors, as well as their roles in tumor growth and metastasis, have been widely described. Recent studies have indicated that the aberrant sialylation is a vital way for tumor cells to escape immune surveillance and keep malignance. In this article, we outline the present state of knowledge on the metabolic pathway of human sialic acids, the function of hypersialylation in tumors, as well as the recent labeling and analytical techniques for sialic acids. It is expected to offer a brief introduction of sialic acid metabolism and provide advanced analytical strategies in sialic acid studies.

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Section: Sialic Acids Enhance Tumor Proliferation and Metastasismentioning

confidence: 99%

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Zhou

Yang

Guan

2020

Cells

132

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“…N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two major sialic acids in mammals [3]. Because of their negative electric charge, sialic acids play crucial roles in a variety of cellular functions, e.g., cell-cell interaction, determining conformation of glycoproteins on cell membranes, and masking antigenic determinants on receptor molecules [4][5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Sialidase NEU1 suppresses progression of human bladder cancer cells by inhibiting fibronectin-integrin α5β1 interaction and Akt signaling pathway

et al. 2020

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Background: Sialic acids are widely distributed in animal tissues, and aberrantly expressed in a variety of cancer types. High expression of sialic acid contributes to tumor aggressiveness by promoting cell proliferation, migration, angiogenesis, and metastasis. Sialidases are responsible for removal of sialic acids from glycoproteins and glycolipids. Methods: N-glycomics of bladder cancer cells were detected by MALDI-TOF mass spectrometry. Sialic acid modification in bladder cancer tissue was determined by lectin blot. The down-regulation of NEU1 in bladder cancer cells was determined by high resolution liquid chromatography mass spectrometry (HR LC-MS). The effects of sialidase NEU1 expression on proliferation and apoptosis of human bladder cancer cells were examined by western blot, RT-PCR, confocal imaging and flow cytometry. Moreover, the function of sialic acids on fibronectinintegrin α5β1 interaction were assayed by immunoprecipitation and ELISA. The importance of NEU1 in tumor formation in vivo was performed using BALB/c-nu mice. Expression of NEU1 in primary human bladder cancer tissue samples was estimated using bladder cancer tissue microarray. Results: (1) Downregulation of NEU1 was primarily responsible for aberrant expression of sialic acids in bladder cancer cells. (2) Decreased NEU1 expression was correlated with bladder cancer progression. (3) NEU1 overexpression enhanced apoptosis and reduced proliferation of bladder cancer cells. (4) NEU1 disrupted FNintegrin α5β1 interaction and deactivated the Akt signaling pathway. (5) NEU1 significantly suppressed in vivo tumor formation in BALB/c-nu mice. Conclusions: Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway. Our observations indicate that NEU1 is an important modulator of the malignant properties of bladder cancer cells, and is a potential therapeutic target for prognosis and treatment of bladder cancer.

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“…High expression of ST6Gal-I is correlated with decreased overall and progression free survival in patients with high-grade serous ovarian carcinoma [9,10], the most common and aggressive subtype [1]. ST6Gal-I regulates tumor cell phenotype by modulating the sialylation, and therefore function, of key receptors that drive malignant cell behaviors [11][12][13][14][15][16][17]. We and others have shown that ST6Gal-I activity confers all of the hallmark features of a CSC including increased expression of canonical CSC markers [18], invasive potential [16,19], tumor-initiating potential [9,20], and resistance to hypoxia, chemotherapeutics, and radiation [14,[20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

et al. 2019

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Background: The ST6Gal-I glycosyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-Imediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. Results: Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including~25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2-6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2-6 sialylation. Conclusions: These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.

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

Cited by 30 publications

References 41 publications

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Sialidase NEU1 suppresses progression of human bladder cancer cells by inhibiting fibronectin-integrin α5β1 interaction and Akt signaling pathway

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

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