α1,4-Linked N-acetylglucosamine suppresses gastric cancer development by inhibiting Mucin-1-mediated signaling.
α1,4-Linked N-acetylglucosamine suppresses gastric cancer development by inhibiting Mucin-1-mediated signaling.
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胃癌是全球癌症死亡的第二大原因，迫切需要对其分子基础有更多的了解。由胃粘膜的幽门腺细胞、粘液颈细胞和贲门腺细胞分泌的胃腺粘蛋白含有独特的O-聚糖，其携带末端α 1，4-连接的N-乙酰葡萄糖胺（αGlcNAc）残基。我们先前报道了αGlcNAc丢失与分化型胃癌患者的不良结局呈正相关。然而，这些结果背后的分子机制仍然知之甚少。在这里，我们研究了αGlcNAc表达上调对分化型胃癌细胞系AGS和MKN 7恶性表型的影响。αGlcNAc生物合成酶异位表达后的上调减弱了体外AGS和MKN 7细胞的细胞增殖、运动性和侵袭性。此外，在异种移植模型中，αGlcNAc过表达显著抑制AGS细胞致瘤性。为了确定这些表型的分子机制，我们研究了AGS细胞中的αGlcNAc结合蛋白，并鉴定了粘蛋白-1（MUC 1）和足糖萼蛋白。这两种蛋白质与αGlcNAc在人胃癌细胞上共定位。我们还发现，αGlcNAc与小鼠正常胃粘膜中的MUC 1结合。当我们评估αGlcNAc与MUC 1结合的作用时，我们发现αGlcNAc阻断半乳糖凝集素-3与MUC 1的结合、MUC 1 C末端的磷酸化以及Src和β-连环蛋白向该C末端的募集。这些结果表明，αGlcNAc通过抑制MUC 1信号转导来调节癌细胞表型。我们先前报道了编码α4GnT的A4 gnt缺陷小鼠完全丧失αGlcNAc，并自发发展为分化型腺癌。此外，αGlcNAc的丢失与分化型胃癌患者的不良结局相关。然而，αGlcNAc缺失导致胃癌发生的分子机制尚不清楚。在这项研究中，我们证明了在2种分化型胃癌细胞系中强制表达αGlcNAc可以减轻恶性表型。我们还表明，αGlcNAc通过与MUC 1结合，降低MUC 1信号传导，起到肿瘤抑制剂的作用。
Gastric cancer is the second leading cause of cancer deaths worldwide, and more understanding of its molecular basis is urgently needed. Gastric gland mucin secreted from pyloric gland cells, mucous neck cells, and cardiac gland cells of the gastric mucosa harbors unique O‐glycans carrying terminal α1,4‐linked N‐acetylglucosamine (αGlcNAc) residues. We previously reported that αGlcNAc loss correlated positively with poor outcomes for patients with differentiated‐type gastric cancer. However, the molecular mechanisms underlying these outcomes remained poorly understood. Here, we examined the effects of upregulated αGlcNAc expression on malignant phenotypes of the differentiated‐type gastric cancer cell lines, AGS and MKN7. Upregulation of αGlcNAc following ectopic expression of its biosynthetic enzyme attenuated cell proliferation, motility, and invasiveness of AGS and MKN7 cells in vitro. Moreover, AGS cell tumorigenicity was significantly suppressed by αGlcNAc overexpression in a xenograft model. To define the molecular mechanisms underlying these phenotypes, we investigated αGlcNAc binding proteins in AGS cells and identified Mucin‐1 (MUC1) and podocalyxin. Both proteins were colocalized with αGlcNAc on human gastric cancer cells. We also found that αGlcNAc was bound to MUC1 in murine normal gastric mucosa. When we assessed the effects of αGlcNAc binding to MUC1, we found that αGlcNAc blocked galectin‐3 binding to MUC1, phosphorylation of the MUC1 C‐terminus, and recruitment of Src and β‐catenin to that C‐terminus. These results suggest that αGlcNAc regulates cancer cell phenotypes by dampening MUC1 signal transduction. We previously reported that A4gnt, which encodes α4GnT, deficient mice completely lost αGlcNAc, and spontaneously developed differentiated‐type adenocarcinoma. Furthermore, loss of αGlcNAc correlated with poor outcome of differentiated‐type gastric cancer patients. However, the molecular mechanisms why loss of αGlcNAc leads to gastric cancer development are poorly understood. In this study, we demonstrate that malignant phenotypes are attenuated by forced expression of αGlcNAc in 2 differentiated‐type gastric cancer cell lines. We also show that αGlcNAc acts as a tumor suppressor by binding to MUC1, decreasing MUC1 signaling.
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