Hypoxia Controls the Glycome Signature and Galectin-8-Ligand Axis to Promote Protumorigenic Properties of Metastatic Melanoma.
Hypoxia Controls the Glycome Signature and Galectin-8-Ligand Axis to Promote Protumorigenic Properties of Metastatic Melanoma.
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DOI：
10.1016/j.jid.2022.07.033
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发表时间：
2023-03
影响因子：
6.5
通讯作者：
Dimitroff, Charles J.
中科院分区：
文献类型：
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作者：
Chakraborty, Asmi;Perez, Mariana;Carroll, Jordan D.;Antonopoulos, Aristotelis;Dell, Anne;Ortega, Liettel;Mohammed, Norhan B. B.;Wells, Michael;Staudinger, Caleb;Griswold, Anthony;Chandler, Kevin B.;Marrero, Cristina;Jimenez, Ramon;Tani, Yoshihiko;Wilmott, James S.;Thompson, John F.;Wang, Wei;Sackstein, Robert;Scolyer, Richard A.;Murphy, George F.;Haslam, Stuart M.;Dimitroff, Charles J.
涉及远处器官的转移性黑色素瘤（MM）患者的预后是严峻的，并且在缺氧条件下茁壮成长的肿瘤起始细胞（TIC）增强了治疗抗性。MM细胞，包括TIC，通过I-分支酶β 1，6 N-乙酰葡糖胺转移酶2的损失表达独特的糖组，其特征在于i-线性聚-N-乙酰乳糖胺。缺氧是否通过调节糖组特征来指导MM TIC的发展仍然未知。在这项研究中，我们探索了MM糖组相关基因的缺氧依赖性改变，发现β 1，6 N-乙酰葡糖胺转移酶2下调，并诱导了半乳糖凝集素（Gal）-8配体轴，涉及细胞外和细胞内Gal-8。低β 1，6 N-乙酰葡糖胺转移酶2水平与不良患者结局相关，患者血清样本中Gal-8升高。MM细胞中β 1，6 N-乙酰葡糖胺转移酶2的抑制上调TIC标志物NGFR/CD 271，而MM细胞内在Gal-8的缺失显著降低NGFR并降低体内TIC活性。细胞外Gal-8优先结合TIC标记物和促转移分子CD 44的N-聚糖上的i-线性聚-N-乙酰基乳糖胺，以及其他受体，并活化促存活因子蛋白激酶B。该研究揭示了缺氧通过加强i-线性聚-N-乙酰乳糖胺和Gal-8表达来控制MM糖组的重要性。该机制研究还揭示了前MM因子NGFR的糖基化依赖性调节，暗示i-线性聚-N-乙酰基乳糖胺和Gal-8是MM的生物标志物和治疗靶标。
The prognosis for patients with metastatic melanoma (MM) involving distant organs is grim, and treatment resistance is potentiated by tumor-initiating cells (TICs) that thrive under hypoxia. MM cells, including TICs, express a unique glycome featuring i-linear poly-N-acetyllactosamines through the loss of I-branching enzyme, β1,6 N-acetylglucosaminyltransferase 2. Whether hypoxia instructs MM TIC development by modulating the glycome signature remains unknown. In this study, we explored hypoxia-dependent alterations in MM glycome–associated genes and found that β1,6 N-acetylglucosaminyltransferase 2 was downregulated and a galectin (Gal)-8eligand axis, involving both extracellular and cell-intrinsic Gal-8, was induced. Low β1,6 N-acetylglucosaminyltransferase 2 levels correlated with poor patient outcomes, and patient serum samples were elevated for Gal-8. Depressed β1,6 N-acetylglucosaminyltransferase 2 in MM cells upregulated TIC marker, NGFR/CD271, whereas loss of MM cell–intrinsic Gal-8 markedly lowered NGFR and reduced TIC activity in vivo. Extracellular Gal-8 bound preferentially to i-linear poly-N-acetyllactosamines on N-glycans of the TIC marker and prometastatic molecule CD44, among other receptors, and activated prosurvival factor protein kinase B. This study reveals the importance of hypoxia governing the MM glycome by enforcing i-linear poly-N-acetyllactosamine and Gal-8 expression. This mechanistic investigation also uncovers glycome-dependent regulation of pro-MM factor, NGFR, implicating i-linear poly-N-acetyllactosamine and Gal-8 as biomarkers and therapeutic targets of MM.
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DOI：
10.1016/b978-012374178-3.10017-1
发表时间：
2009-01-01
期刊：
HYALURONAN IN CANCER BIOLOGY, 1ST EDITION
影响因子：
--
作者：
Gebhardt, Carl;Averbeck, Marco;Simon, Jan C.
通讯作者：
Simon, Jan C.
影响因子：
5.7
作者：
Bertelli, Adriano;Sanmarco, Liliana M.;Leguizamon, Maira S.
通讯作者：
Leguizamon, Maira S.
影响因子：
3
作者：
Bidon-Wagner, N;Le Pennec, JP
通讯作者：
Le Pennec, JP
DOI：
10.1016/j.bbamcr.2019.03.010
发表时间：
2019-08-01
影响因子：
5.1
作者：
Ferragut, Fatima;Cagnoni, Alejandro J.;Elola, Maria T.
通讯作者：
Elola, Maria T.
影响因子：
64.8
作者：
通讯作者：
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