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

• Published in: British journal of cancer 2019-11, Vol.121 (11), p.944-953
• Main Authors: Hamester, Fabienne, Legler, Karen, Wichert, Beatrice, Kelle, Nicole, Eylmann, Kathrin, Rossberg, Maila, Ding, Yi, Kürti, Sascha, Schmalfeldt, Barbara, Milde-Langosch, Karin, Oliveira-Ferrer, Leticia
• Format: Article
• Language: English
• Subjects: 631/67/1517/1709; 631/67/1857; 631/80/458/1524; Adhesion; alpha-Mannosidase - genetics; alpha-Mannosidase - metabolism; Antigens, CD - metabolism; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules, Neuronal - metabolism; Cell aggregation; Cell Aggregation - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Disease-Free Survival; Drug Resistance; Epidemiology; Female; Fetal Proteins - metabolism; Gene Knockout Techniques; Glycosylation; Golgi apparatus; Golgi Apparatus - metabolism; Humans; Lymph nodes; Mannosidase; Medical prognosis; Metastases; Middle Aged; Molecular Medicine; N-glycans; Oncology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Polysaccharides; Prognosis; Retrospective Studies; RNA, Messenger - genetics; Transfection; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-019-0607-2

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.