ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide, and early diagnosis is vital to improving prognoses. We explored the diagnostic potential of a multiplex autoantibody panel as a biomarker for the detection of CRC by ELISA. METHODS: In total, 192 serum samples (92 CRC and 100 matched controls) were tested against a panel of 12 tumor-associated antigens (TAAs): RPH3AL, RPL36, SLP2, p53, survivin, ANAXA4, SEC61B, CCCAP, NYCO16, NMDAR, PLSCR1, and HDAC5. Individual and combined autoantibody signatures were examined. RESULTS: Compared to individual autoantibody markers, the combinations of TAAs provided better discrimination between tumorous and normal sera. The overall sensitivity of a selected panel of four antibodies (anti-SLP2, -p53, -SEC61B, and -PLSCR1) was 64.1%, with a specificity of 80% that increased to 83.7% when carcinoembryonic antigen (CEA) measurement was added. Furthermore, the sensitivity of the panel of four antibodies for early and advanced stages of CRC was 66.7% and 62%, increasing to 88.3% and 84%, respectively, when CEA was added. CONCLUSIONS: We identified a panel of four antibodies as a promising diagnostic biomarker for the detection of CRC.
Subject(s)
Antigens, Neoplasm/genetics , Autoantibodies/blood , Biomarkers, Tumor/blood , Colorectal Neoplasms/diagnosis , Immunoassay , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/immunology , Blood Proteins/genetics , Blood Proteins/immunology , Carcinoembryonic Antigen/genetics , Carcinoembryonic Antigen/immunology , Case-Control Studies , Colorectal Neoplasms/blood , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Early Detection of Cancer/methods , Female , Humans , Male , Membrane Proteins/genetics , Membrane Proteins/immunology , Middle Aged , Neoplasm Staging , Phospholipid Transfer Proteins/genetics , Phospholipid Transfer Proteins/immunology , Prognosis , SEC Translocation Channels/genetics , SEC Translocation Channels/immunology , Sensitivity and Specificity , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/immunologyABSTRACT
Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single-amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61α. Quantitative proteomics reveals that during T cell activation, mycolactone-mediated Sec61 blockade affects a selective subset of secretory proteins including key signal-transmitting receptors and adhesion molecules. Expression of mutant Sec61α in mycolactone-treated T cells rescued their homing potential and effector functions. Furthermore, when expressed in macrophages, the mycolactone-resistant mutant restored IFN-γ receptor-mediated antimicrobial responses. Thus, our data provide definitive genetic evidence that Sec61 is the host receptor mediating the diverse immunomodulatory effects of mycolactone and identify Sec61 as a novel regulator of immune cell functions.
