Abstract
The absence of highly specific markers for malignant mesothelioma (MM) has served an obstacle for its diagnosis and development of molecular-targeting therapy against MM. Here, we show that a novel mucin-like membrane protein, sialylated protein HEG homolog 1 (HEG1), is a highly specific marker for MM. A monoclonal antibody against sialylated HEG1, SKM9-2, can detect even sarcomatoid and desmoplastic MM. The specificity and sensitivity of SKM9-2 to MM reached 99% and 92%, respectively; this antibody did not react with normal tissues. This accurate discrimination by SKM9-2 was due to the recognition of a sialylated O-linked glycan with HEG1 peptide. We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs. Taken together, our results indicate that sialylated HEG1 may be useful as a diagnostic and therapeutic target for MM.
Highlights
These markers often have difficulty discriminating epithelioid MM from metastatic tumors or sarcomatoid MM from some sarcomas
The monoclonal antibodies (mAbs) SKM9-2 was obtained by immunizing epithelioid malignant pleural mesothelioma (MPM) cell lines to mice, and screening for mAb clones that recognized MPM cell lines but not a lung cancer cell line (Supplementary Methods and Supplementary Fig. 1)
SKM9-2 antigen was detected in 92% of MPMs, and the positive rate exceeded those for other MM diagnostic markers, viz. calretinin (80%), cytokeratin 5/6 (CK5/6) (78%), podoplanin (82%), nucleus Wilms’ tumor gene product 1 (WT-1) (87%), and mesothelin (79%)
Summary
These markers often have difficulty discriminating epithelioid MM from metastatic tumors or sarcomatoid MM from some sarcomas. Immature glycans are produced by irregular processes of carbohydrate chain synthesis in tumor cells, and are attached in clusters on mucin-like proteins[12,13,14]. The combined recognition of a mucin-like protein and its irregular glycan attachment can detect malignant tumor cells accurately[16]. A tumor-specific mucin-like membrane protein can become a target for antibody-utilized immunotherapy[17] or drug inhibition of cell proliferation[18,19,20,21]. If a mucin-like membrane protein with characteristic glycosylation is found on MM, it could become a specific target for accurate MM diagnosis or molecular-targeting therapy. We show that sialylated HEG1, which we identified as a novel mucin-like membrane protein, is a mesothelioma-related antigen, and that HEG1 expression supports the survival and proliferation of mesothelioma cells. Sialylated HEG1 may be a worthwhile target for MM diagnosis and therapy
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