文章：

细胞外唾液转移酶ST6GAL1在乳腺肿瘤细胞生长和侵袭中的作用

Extracellular sialyltransferase ST6GAL1 in breast tumor cell growth and invasiveness 

原文发布日期：2022-06-08 

英文摘要：

The sialyltransferase ST6GAL1 that adds α2–6 linked sialic acids to N-glycans of cell surface and secreted glycoproteins is prominently associated with many human cancers. Tumor-native ST6GAL1 promotes tumor cell behaviors such as invasion and resistance to cell stress and chemo- and radio-treatments. Canonically, ST6GAL1 resides in the intracellular secretory apparatus and glycosylates nascent glycoproteins in biosynthetic transit. However, ST6GAL1 is also released into the extracellular milieu and extracellularly remodels cell surface and secreted glycans. The impact of this non-canonical extrinsic mechanism of ST6GAL1 on tumor cell pathobiology is not known. We hypothesize that ST6GAL1 action is the combined effect of natively expressed sialyltransferase acting cell-autonomously within the ER-Golgi complex and sialyltransferase from extracellular origins acting extrinsically to remodel cell-surface glycans. We found that shRNA knockdown of intrinsic ST6GAL1 expression resulted in decreased ST6GAL1 cargo in the exosome-like vesicles as well as decreased breast tumor cell growth and invasive behavior in 3D in vitro cultures. Extracellular ST6GAL1, present in cancer exosomes or the freely soluble recombinant sialyltransferase, compensates for insufficient intrinsic ST6GAL1 by boosting cancer cell proliferation and increasing invasiveness. Moreover, we present evidence supporting the existence novel but yet uncharacterized cofactors in the exosome-like particles that potently amplify extrinsic ST6GAL1 action, highlighting a previously unknown mechanism linking this enzyme and cancer pathobiology. Our data indicate that extracellular ST6GAL1 from remote sources can compensate for cellular ST6GAL1-mediated aggressive tumor cell proliferation and invasive behavior and has great clinical potential for extracellular ST6GAL1 as these molecules are in the extracellular space should be easily accessible targets. 

摘要翻译：

将α2-6连接唾液酸添加到细胞表面及分泌型糖蛋白N-聚糖的唾液酸转移酶ST6GAL1，与多种人类癌症显著相关。肿瘤自身表达的ST6GAL1能够促进肿瘤细胞侵袭、抵抗细胞应激以及化学和放射治疗等行为。经典理论认为，ST6GAL1位于细胞内分泌器中，在生物合成过程中对新生糖蛋白进行糖基化修饰。然而，ST6GAL1也会被释放到细胞外环境中，并在胞外重塑细胞表面及分泌型聚糖。这种非常规的外源性ST6GAL1作用机制对肿瘤细胞病理生物学的影响尚不明确。我们提出假说：ST6GAL1的作用是内源性表达唾液酸转移酶在ER-高尔基复合体内通过细胞自主作用，与细胞外来源唾液酸转移酶通过外源性作用重塑细胞表面聚糖的共同效应。研究发现，通过shRNA敲低内源性ST6GAL1表达后，类外泌体囊泡中ST6GAL1含量降低，同时三维体外培养中乳腺肿瘤细胞的生长和侵袭行为减弱。而存在于癌症外泌体或自由可溶性重组唾液酸转移酶中的细胞外ST6GAL1，可通过促进癌细胞增殖和增强侵袭能力来补偿内源性ST6GAL1的不足。更重要的是，我们发现了类外泌体颗粒中存在尚未被表征的新型辅助因子，能有效增强外源性ST6GAL1的作用，这揭示了该酶与癌症病理生物学之间存在前所未有的新机制。我们的数据表明，来自远源的细胞外ST6GAL1可补偿细胞ST6GAL1介导的侵袭性肿瘤细胞增殖行为，且细胞外ST6GAL1分子具有重要临床潜力——由于这些分子存在于细胞外空间，它们有望成为易于接近的治疗靶点。

原文链接：

Extracellular sialyltransferase st6gal1 in breast tumor cell growth and invasiveness