Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis.
Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis.
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细胞外Serglycin以自分泌方式上调CD44受体，以通过相互激活MAPK/β-catenin轴来维持鼻咽癌细胞中的自我更新。
DOI：
10.1038/cddis.2016.287
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发表时间：
2016-11-03
影响因子：
9
通讯作者：
Huang B
中科院分区：
文献类型：
--
作者：
Chu Q;Huang H;Huang T;Cao L;Peng L;Shi S;Zheng L;Xu L;Zhang S;Huang J;Li X;Qian C;Huang B
Serglycin是一种蛋白多糖，最早被发现由造血细胞分泌。舍甘氨酸作为细胞外基质（ECM）成分，促进鼻咽癌（NPC）转移，是鼻咽癌独立的不利预后指标。谢尔甘霉素在癌症进展中作用的详细机制仍有待阐明。在这里，我们报道了鼻咽癌细胞中serglycin的敲低抑制了细胞球的形成和肿瘤的播种能力。Serglycin下调可增强高转移性鼻咽癌细胞对化疗的敏感性。据报道，serglycin是干细胞标志物CD44的一种新型配体。有趣的是，我们发现serglycin在鼻咽组织和NPC细胞系中的表达与CD44呈正相关。进一步研究发现，CD44是serglycin信号通路的erk依赖性下游效应因子，serglycin激活MAPK/β-catenin轴，诱导CD44受体在正反馈回路中表达。综上所述，我们的新发现表明，ECM serglycin通过与CD44相互作用并激活MAPK/β-catenin通路，上调CD44受体的表达以维持鼻咽癌的干细胞性，从而导致鼻咽癌细胞耐药。这些发现提示，干预serglycin/CD44轴及下游信号通路是靶向鼻咽癌干细胞治疗的合理策略。
Serglycin is a proteoglycan that was first found to be secreted by hematopoietic cells. As an extracellular matrix (ECM) component, serglycin promotes nasopharyngeal carcinoma (NPC) metastasis and serves as an independent, unfavorable NPC prognostic indicator. The detailed mechanism underlying the roles of serglycin in cancer progression remains to be clarified. Here, we report that serglycin knockdown in NPC cells inhibited cell sphere formation and tumor seeding abilities. Serglycin downregulation enhanced high-metastasis NPC cell sensitivity to chemotherapy. It has been reported that serglycin is a novel ligand for the stem cell marker CD44. Interestingly, we found a positive correlation between serglycin expression and CD44 in nasopharyngeal tissues and NPC cell lines. Further study revealed that CD44 was an ERK-dependent downstream effector of serglycin signaling, and serglycin activated the MAPK/β-catenin axis to induce CD44 receptor expression in a positive feedback loop. Taken together, our novel findings suggest that ECM serglycin upregulated CD44 receptor expression to maintain NPC stemness by interacting with CD44 and activating the MAPK/β-catenin pathway, resulting in NPC cell chemoresistance. These findings suggest that the intervention of serglycin/CD44 axis and downstream signaling pathway is a rational strategy for targeting NPC cancer stem cell therapy.