Early detection of hepatocellular carcinoma using autoantibody profiles from a panel of tumor-associated antigens

Koziol, James A.; Imai, Haruhiko; Dai, Liping; Zhang, Jianying; Tan, Eng M.

doi:10.1007/s00262-018-2135-y

Cited by 22 publications

(19 citation statements)

References 16 publications

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“…Autoantibodies against these TAAs are produced when the antigenic peptides presented on human leukocyte antigen (HLA) class I molecules exceed the TCR threshold, which is required for CD4+ T cell activation [28]. In this study, we provided evidence for the hypothesis that p62/IMP2 is aberrantly overexpressed in both HCC tissues and cell lines, and our IHC results showed that the expression of p62/IMP2 reached a high level in the early stage of cancer, which is consistent with a previous study showing that autoantibodies can be detected early in HCC [29]. Considering that the overall survival time is less than 1 year for late-stage HCC patients (based on the BCLC staging system), early diagnosis is most important for improving the prognosis of patients.…”

Section: Discussionsupporting

confidence: 89%

Overexpression of p62/IMP2 can Promote Cell Migration in Hepatocellular Carcinoma via Activation of the Wnt/β-Catenin Pathway

Xing

Wang

et al. 2019

Cancers

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p62/IMP2 is an oncofetal protein that was first reported as a tumor-associated antigen in hepatocellular carcinoma (HCC). In our previous studies, we demonstrated a high frequency of p62/IMP2 autoantibodies appearing in various types of cancer. Therefore, we hypothesize that p62/IMP2 plays an important role in the progression of HCC, although the mechanism remains to be explored. In this study, we evaluated the expression of p62/IMP2 protein both in human tissues and liver cancer cell lines by immunohistochemistry and western blotting analysis and found that p62/IMP2 protein is overexpressed in human HCC tissue in comparison to normal human liver tissue. To explore the role that p62/IMP2 plays in HCC, p62/IMP2 was knocked out in two p62/IMP2-positive liver cancer cell lines (SNU449 and HepG2). Due to the low expression level of p62/IMP2 in SNU449, we overexpressed p62/IMP2 in this cell line. We subsequently demonstrated that high expression of p62/IMP2 in both cell lines can promote cell migration and invasion abilities in vitro by activating the Wnt/β-catenin pathway. We also used the Wnt/β-catenin pathway inhibitor, XAV 939, and a phosphoproteome assay to confirm our findings. Conclusion: Our results suggest that p62/IMP2 is an essential regulator of Wnt signaling pathways and plays an important role in HCC progression and metastasis.Cancers 2020, 12, 7 2 of 16 with various mRNA to regulate their stability, translatability, and localization [9]. IMPs are considered oncofetal proteins, and their overexpression in various types of cancers has been reported [8,9]. p62/IMP2 was originally reported as a tumor-associated antigen (TAA) in HCC [10]. The high frequency of anti-p62/IMP2 autoantibody occurrence in the serum samples from various types of cancer patients implies that p62/IMP2 may play a role in cancer progression [11][12][13][14]. Several cancer-associated p62/IMP2 target mRNAs have been identified. They include CCN2 mRNA [15], IGF2 mRNA [7], and c-Myc mRNA [15]. Some studies have reported that p62/IMP2 is involved in carcinogenesis. When phosphorylated by mTOR, p62/IMP2 stabilizes HMGA1 and stimulates the expression of IGF2, potentially leading to increased cancer cell proliferation [16]. By activating the IGF2/PI3K/Akt pathway, p62/IMP2 can conceivably promote proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) of glioblastoma cells [17]. Recently, p62/IMP2 has been shown to enhance the migration ability of cancer cells and promote cancer metastasis. A cluster of p62/IMP2 targets (LIMS2, TRIM54, and LAMB2) are considered to be involved in the downstream effects of p62/IMP2 expression that indeed increased cell migration, cell adhesion, and cytoskeleton remodeling, which can promote the metastatic behavior of cancer cells [18]. A recent study from our group demonstrated that the overexpressed p62/IMP2 enhances the expression of β-catenin and CTGF, which therefore heightens cell migration and reduces cell adhesion in breast cancer cells [15]. Another group also reported that p...

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Section: Discussionsupporting

confidence: 89%

Overexpression of p62/IMP2 can Promote Cell Migration in Hepatocellular Carcinoma via Activation of the Wnt/β-Catenin Pathway

Xing

Wang

et al. 2019

Cancers

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“…Among these 19 AAbs, 17 were also present in the discovery HuProt array and satisfied 1-2 criteria. Another 2 AAbs, CENPF [16] and CDKN2A [5], were absent in the discovery HuProt array. Alternatively, more samples were enrolled in the test phase (II) and validation phase (III), which would help to accurately evaluate the distinguishing capacity of these AAbs.…”

Section: Aab Screening For Construction Of Hcc-focused Arraysmentioning

confidence: 99%

“…For example, DHCR24 AAb was identified as a novel biomarker for disease progression of hepatitis C [4]. Likewise, it has been reported that AAbs against HCC1, CDKN2A, p53, CIP2A, and survivin could indicate the presence of HCC prior to clinical diagnosis [5]. In another study, AAbs against NPM-1, 14-3-3 zeta, and MDM2 were suggested to have diagnostic value for AFP-negative HCC patients (AFP < 20 ng/mL; AFP − HCC) [6].…”

Section: Introductionmentioning

confidence: 99%

Autoantibody signature in hepatocellular carcinoma using seromics

et al. 2020

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Background: Alpha-fetoprotein (AFP) is a widely used biomarker for hepatocellular carcinoma (HCC) early detection. However, low sensitivity and false negativity of AFP raise the requirement of more effective early diagnostic approaches for HCC. Methods: We employed a three-phase strategy to identify serum autoantibody (AAb) signature for HCC early diagnosis using protein array-based approach. A total of 1253 serum samples from HCC, liver cirrhosis, and healthy controls were prospectively collected from three liver cancer centers in China. The Human Proteome Microarray, comprising 21,154 unique proteins, was first applied to identify AAb candidates in discovery phase (n = 100) and to further fabricate HCCfocused arrays. Then, an artificial neural network (ANN) model was used to discover AAbs for HCC detection in a test phase (n = 576) and a validation phase (n = 577), respectively. Results: Using HCC-focused array, we identified and validated a novel 7-AAb panel containing CIAPIN1, EGFR, MAS1, SLC44A3, ASAH1, UBL7, and ZNF428 for effective HCC detection. The ANN model of this panel showed improvement of sensitivity (61.6-77.7%) compared to AFP (cutoff 400 ng/mL, 28.4-30.7%). Notably, it was able to detect AFP-negative HCC with AUC values of 0.841-0.948. For early-stage HCC (BCLC 0/A) detection, it outperformed AFP (cutoff 400 ng/mL) with approximately 10% increase in AUC. Conclusions: The 7-AAb panel provides potentially clinical value for non-invasive early detection of HCC, and brings new clues on understanding the immune response against hepatocarcinogenesis.

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“…The most common primary hepatic malignancy is hepatocellular carcinoma (HCC), and it is predicted by a gold standard diagnostic biomarker AFP, although the lack of sensitivity 13,14 has challenged its use. There have been continuous efforts for the discovery of HCC-associated autoantibody biomarkers 15,16 to use as early diagnostic biomarkers, and several tumor-associated autoantibodies were recently suggested as an early predictor of HCC before diagnosis 17 . The multiplex detection of tumor-associated biomarkers also can enhance the accuracy of cancer diagnosis, which encourages further investigation of reliable autoantibody biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Serum anti-EIF3A autoantibody as a potential diagnostic marker for hepatocellular carcinoma

Heo

Hwang

Lee

et al. 2019

Sci Rep

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Tumor-associated autoantibodies are promising diagnostic biomarkers for early detection of tumors. We have screened a novel tumor-associated autoantibody in hepatocellular carcinoma (HCC) model mice. Its target antigen was identified as eukaryotic translation initiation factor 3 subunit A (EIF3A) by proteomic analysis, and the elevated expression of EIF3A in HCC tissues of tumor model mice as well as human patients was shown. Also, its existence in tumor-derived exosomes was revealed, which seem to be the cause of tumor-associated autoantibody production. To use serum anti-EIF3A autoantibody as biomarker, ELISA detecting anti-EIF3A autoantibody in human serum was performed using autoantibody-specific epitope. For the sensitive detection of serum autoantibodies its specific conformational epitopes were screened from the random cyclic peptide library, and a streptavidin antigen displaying anti-EIF3A autoantibody-specific epitope, XC90p2(- C PVRSGFP C -), was used as capture antigen. It distinguished patients with HCC (n = 102) from healthy controls (n = 0285) with a sensitivity of 79.4% and specificity of 83.5% (AUC = 0.87). Also, by simultaneously detecting with other HCC biomarkers, including alpha-fetoprotein, HCC diagnostic sensitivity improved from 79.4% to 85%. Collectively, we suggest that serum anti-EIF3A autoantibody is a useful biomarker for the diagnosis of HCC and the combinational detection of related biomarkers can enhance the accuracy of the cancer diagnosis.

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Early detection of hepatocellular carcinoma using autoantibody profiles from a panel of tumor-associated antigens

Abstract: We believe these findings warrant further study of anti-TAA profiles as biomarkers for primary or early diagnosis of HCC.

Cited by 22 publications

References 16 publications

Overexpression of p62/IMP2 can Promote Cell Migration in Hepatocellular Carcinoma via Activation of the Wnt/β-Catenin Pathway

Overexpression of p62/IMP2 can Promote Cell Migration in Hepatocellular Carcinoma via Activation of the Wnt/β-Catenin Pathway

Autoantibody signature in hepatocellular carcinoma using seromics

Serum anti-EIF3A autoantibody as a potential diagnostic marker for hepatocellular carcinoma

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