High frequency of LMAN1 abnormalities in colorectal tumors with microsatellite instability.
Glycosyl epitopes have been identified as tumor-specific markers in colorectal tumors and various lines of evidence indicate the significance of altered synthesis, transport, and secretion of glycoproteins in tumorigenesis. However, aberrant glycosylation has been largely ignored in microsatellite unstable (MSI-H) colorectal tumors. Therefore, we analyzed mutation frequencies of genes of the cellular glycosylation machinery in MSI-H tumors, focusing on frameshift mutations in coding MNRs (cMNRs). Among 28 candidate genes, LMAN1/ERGIC53, a mannose-specific lectin mediating endoplasmatic reticulum (ER)-to-Golgi transit of glycosylated proteins, showed high mutation frequency in MSI-H colorectal cancer cell lines (52%; 12 of 23), carcinomas (45%; 72 of 161), and adenomas (40%; 8 of 20). Biallelic mutations were observed in 17% (4 of 23) of MSI-H colorectal cancer cell lines. LMAN1 was found to be transcribed but truncated protein remained undetectable in these LMAN1-mutant cell lines. Immunohistochemical and molecular analysis of LMAN1-mutated carcinomas and adenomas revealed regional loss of LMAN1 expression due to biallelic LMAN1 cMNR frameshift mutations. In LMAN1-deficient colorectal cancer cell lines, secretion of the LMAN1 client protein alpha-1-antitrypsin (A1AT), an inhibitor of angiogenesis and tumor growth, was significantly impaired but could be restored upon LMAN1 re-expression. These results suggest that LMAN1 mutational inactivation is a frequent and early event potentially contributing to MSI-H tumorigenesis.
Roeckel
Nina
N
Department of Applied Tumor Biology, Institute of Pathology, University Hospital, Im Neuenheimer Feld 220/221, Heidelberg, Germany.
Woerner
Stefan M
SM
Kloor
Matthias
M
Yuan
Yan-Ping
YP
Patsos
Georgios
G
Gromes
Roland
R
Kopitz
Juergen
J
Gebert
Johannes
J
D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D015870:Gene Expression; D006801:Humans; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D053842:Microsatellite Instability; D012333:RNA, Messenger / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000378:metabolism
C084004:LMAN1 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D012333:RNA, Messenger; D000515:alpha 1-Antitrypsin