Abstract
Tumor-associated (TA) autoantibodies have been identified at the early tumor stage before developing clinical symptoms, which holds hope for early cancer diagnosis. We identified a TA autoantibody from HBx-transgenic (HBx-tg) hepatocellular carcinoma (HCC) model mouse, characterized its target antigen, and examined its relationship to human HCC. The mimotopes corresponding to the antigenic epitope of TA autoantibody were screened from a random cyclic peptide library and used for the detection of serum TA autoantibody. The target antigen of the TA autoantibody was identified as an oncogenic bi-functional purine biosynthesis protein, ATIC. It was upregulated in liver cancer tissues of HBx-tg mouse as well as human HCC tissues. Over-expressed ATIC was also secreted extracellularly via the cancer-derived exosomes, which might cause auto-immune responses. The cyclic peptide mimotope with a high affinity to anti-ATIC autoantibody, CLPSWFHRC, distinguishes between serum samples from HCC patients and healthy subjects with 70.83% sensitivity, 90.68% specificity (AUC = 0.87). However, the recombinant human ATIC protein showed a low affinity to anti-ATIC autoantibody, which may be incompatible as a capture antigen for serum TA autoantibody. This study indicates that anti-ATIC autoantibody can be a potential HCC-associated serum biomarker and suggests that autoantibody biomarker’s efficiency can be improved by using antigenic mimicry to native antigens present in vivo.
Highlights
Cancer is the second leading cause of death globally and the most critical barrier to increasing life expectancy in every country of the world in the 21st century [1]
H-ras12V transgenic or HBx-transgenic mice have proven to be suitable for the human hepatocellular carcinoma (HCC) model [20,21]
It detected the same antigen in non-transgenic mice; its expression was higher in tumor tissues about three-fold (p < 0.0001; Figure 1B), which shows that the overexpression of XC154 antigen is related to tumorigenesis
Summary
Cancer is the second leading cause of death globally and the most critical barrier to increasing life expectancy in every country of the world in the 21st century [1]. General awareness of the risk factors for cancer and early cancer diagnosis have improved survival. It is crucial and urgent to identify more effective and less invasive tumor markers, guiding early diagnosis and therapeutic strategies for individual patients. The various abnormal substances produced by cancer cells can be antigenic, which are no longer recognized as self. The immune system responds to these non-self antigens, producing specific autoantibodies. Tumor-associated (TA) autoantibodies have been observed in patients with various tumors, including breast [4], prostate [5,6], lung [7], colorectal [8], ovarian [9,10], and liver [11], and have become of interest as cancer biomarkers because they can be detected in serum via minimally invasive blood collection [3]
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