Loss of GCNT2/I-branched glycans enhances melanoma growth and survival.
Loss of GCNT2/I-branched glycans enhances melanoma growth and survival.
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DOI：
10.1038/s41467-018-05795-0
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发表时间：
2018-08-22
影响因子：
16.6
通讯作者：
Dimitroff CJ
中科院分区：
文献类型：
--
作者：
Sweeney JG;Liang J;Antonopoulos A;Giovannone N;Kang S;Mondala TS;Head SR;King SL;Tani Y;Brackett D;Dell A;Murphy GF;Haslam SM;Widlund HR;Dimitroff CJ
与未转化的癌细胞相比，癌细胞的细胞表面糖链经常发生变化。然而，多糖在癌症发生和发展中的功能贡献仍然知之甚少。在这里，通过对所有癌症谱系的基于表达的分析，我们发现黑色素瘤在糖基化相关基因中表现出显著的转录变化。这一基因特征表明，与正常黑素细胞相比，黑色素瘤下调了I-分支糖基转移酶GCNT2，导致细胞表面I-分支糖链的丢失。我们发现GCNT2与临床进展呈负相关，GCNT2的缺失增加了黑色素瘤异种移植瘤的生长，促进了克隆形成，并提高了细胞存活率。相反，过表达GCNT2减少了异种黑色素瘤的生长，抑制了克隆形成，并增加了细胞死亡。更有针对性的分析显示，经GCNT2修饰的两个具有代表性的糖蛋白家族，胰岛素样生长因子受体和整合素的信号反应减少。总体而言，这些研究揭示了多糖结构的细微变化如何调节几种与恶性肿瘤相关的途径，并改变黑色素瘤的信号、生长和生存。癌细胞上异常的糖基化模式促进了几种促肿瘤功能，包括促进肿瘤细胞的增殖。在这里，作者提供的数据显示，黑色素瘤细胞下调GCNT2，从而导致I-分支多糖的丢失；这导致扩展的I-线性多糖的形成，并通过增加黑色素瘤的生长，部分是通过IGF-1和细胞外基质诱导的信号。
Cancer cells often display altered cell-surface glycans compared to their nontransformed counterparts. However, functional contributions of glycans to cancer initiation and progression remain poorly understood. Here, from expression-based analyses across cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This gene signature revealed that, compared to normal melanocytes, melanomas downregulate I-branching glycosyltransferase, GCNT2, leading to a loss of cell-surface I-branched glycans. We found that GCNT2 inversely correlated with clinical progression and that loss of GCNT2 increased melanoma xenograft growth, promoted colony formation, and enhanced cell survival. Conversely, overexpression of GCNT2 decreased melanoma xenograft growth, inhibited colony formation, and increased cell death. More focused analyses revealed reduced signaling responses of two representative glycoprotein families modified by GCNT2, insulin-like growth factor receptor and integrins. Overall, these studies reveal how subtle changes in glycan structure can regulate several malignancy-associated pathways and alter melanoma signaling, growth, and survival. Aberrant glycosylation patterns on cancer cells promote several pro-tumorigenic functions, including enhancing tumor cell proliferation. Here the authors provide data that show melanoma cells downregulate GCNT2 with consequent loss of I-branched glycans; this leads to the formation of extended i-linear glycans and enhances melanoma growth via increases, in part, by IGF-1- and extracellular matrix-induced signaling.
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影响因子：
64.5
作者：
Dennis JW;Nabi IR;Demetriou M
通讯作者：
Demetriou M
DOI：
10.1111/j.1600-0749.2006.00322.x
发表时间：
2006-08-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
DOI：
10.1073/pnas.77.2.1039
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CIFONE, MA;FIDLER, IJ
通讯作者：
FIDLER, IJ
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3
作者：
Gu, JG;Taniguchi, N
通讯作者：
Taniguchi, N