Prognostic relevance of the Golgi mannosidase MAN1A1 in ovarian cancer: impact of N-glycosylation on tumour cell aggregation

Fabienne Hamester,Barbara Schmalfeldt,Karen Legler,Nicole Kelle,Maila Rossberg,Leticia Oliveira-Ferrer,Kathrin Eylmann,Yi Ding,Karin Milde-Langosch,Sascha Kürti,Beatrice Wichert

doi:10.1038/s41416-019-0607-2

Fabienne Hamester, Barbara Schmalfeldt + Show 9 more

Open Access

https://doi.org/10.1038/s41416-019-0607-2

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Abstract

BackgroundMaturation 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.MethodsWe 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.ResultsPatients 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.ConclusionsOur 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.

Highlights

Maturation of complex N-glycans involves the action of Golgi mannosidases and plays a major role in cancer progression
MAN1A1 expression in SKOV3 control cells was defined as 100% for statistical analysis
An additional band appeared around 60 kDa in most tumour samples, partly in form of a double band, whereas this could not be detected in SKOV3

Summary

Introduction

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. 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. Aberrant O- and N-glycans are frequently found due to disturbed glycosylation and aberrant expression of glycosylation enzymes.[3]

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