Prognostic relevance of the Golgi mannosidase MAN1A1 in ovarian cancer: impact of N-glycosylation on tumour cell aggregation.,British Journal of Cancer

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Prognostic relevance of the Golgi mannosidase MAN1A1 in ovarian cancer: impact of N-glycosylation on tumour cell aggregation.
British Journal of Cancer ( IF 6.4 ) Pub Date : 2019-10-29 , DOI: 10.1038/s41416-019-0607-2
Fabienne Hamester ₁ , Karen Legler ₁ , Beatrice Wichert ₁ , Nicole Kelle ₁ , Kathrin Eylmann ₁ , Maila Rossberg ₁ , Yi Ding ₁ , Sascha Kürti ₁ , Barbara Schmalfeldt ₁ , Karin Milde-Langosch ₁ , Leticia Oliveira-Ferrer ₁

Affiliation

Background

Maturation of complex N-glycans involves the action of Golgi mannosidases and plays a major role in cancer progression. We recently showed a favourable prognostic role of α-mannosidase MAN1A1 in breast cancer mainly caused by alteration of certain adhesion molecules.

Methods

We analysed the protein expression of MAN1A1 in ovarian cancer (n = 204) using western blot and studied the impact of MAN1A1 itself and of MAN1A1-related glycosylation on the prognostic relevance of two adhesion molecules. Functional consequences of mannosidase inhibition using kifunensine and MAN1A1 knock out were investigated in ovarian cancer cells in vitro.

Results

Patients with high MAN1A1 expression in tumours showed significantly shorter RFS than those with low-MAN1A1 levels. Moreover, high MAN1A1 expression correlated significantly with advanced stage, lymph node involvement and distant metastasis. Further, the glycosylated adhesion molecule ALCAM reveals a significant adverse prognostic effect only in the presence of high MAN1A1 expression. In spheroid-formation assays, mannosidase inhibition and especially MAN1A1 knock out led to strong reduction of tumour cell aggregation.

Conclusions

Our study demonstrates the unfavourable prognostic role of MAN1A1 in ovarian cancer, probably caused by an altered ability of spheroid formation, and the strong influence of this glycosylation enzyme on the prognostic impact of ALCAM.

中文翻译：

高尔基甘露糖苷酶MAN1A1在卵巢癌中的预后相关性：N-糖基化对肿瘤细胞聚集的影响。

背景

复杂的N-聚糖的成熟涉及高尔基甘露糖苷酶的作用，并在癌症进展中起主要作用。最近，我们显示了α-甘露糖苷酶MAN1A1在乳腺癌中的有利预后作用，其主要由某些粘附分子的改变引起。

方法

我们使用蛋白质印迹分析了卵巢癌（n = 204）中MAN1A1的蛋白表达，并研究了MAN1A1本身和MAN1A1相关糖基化对两个黏附分子预后相关性的影响。在体外卵巢癌细胞中研究了使用kifunensine和MAN1A1敲除抑制甘露糖苷酶的功能后果。

结果

在肿瘤中具有高MAN1A1表达的患者显示的RFS明显低于那些具有低MAN1A1水平的患者。此外，MAN1A1的高表达与晚期，淋巴结受累和远处转移密切相关。此外，仅在MAN1A1高表达的情况下，糖基化粘附分子ALCAM才显示出显着的不良预后作用。在球体形成测定中，甘露糖苷酶抑制，尤其是MAN1A1敲除导致肿瘤细胞聚集的强烈减少。