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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Alpha-fetoprotein (AFP) is considered as a diagnostic and prognostic tumorous marker for HCC, and up to 70% of HCC patients showed elevated serum levels of AFP. In the past two decades, evidences have shown that AFP not only is a tumorous biomarker for diagnosing HCC, but also plays a very complicated role in regulating proliferation, apoptosis, and autophagy and inhibiting the immune response of cells. Because AFP is significantly elevated during hepatocarcinogenesis, the role of AFP in the development of HCC is a scientific problem worthy of further exploration. In this review, we reviewed the effects of AFP on hepatocyte malignant transformation and the underlying mechanisms involved in the progression of HCC.

The aim of this study was to develop an avidin-modified macromolecular lipid magnetic sphere and its application in differential diagnosis of liver disease and liver cancer. Lectin-modified macromolecular lipid magnetic spheres were prepared by thin-film hydration method using lentil lectin derivatives (LCA-HQ) and cholesterol as raw materials. Alpha-fetoprotein variants (AFP-L3) in serum from healthy people, liver disease and liver cancer patients were isolated using the prepared lectin-modified macromolecular lipid magnetic spheres, and alpha-fetoprotein (AFP) and AFP-L3 were detected by fully automatic time-resolved fluorescence immunoassay. The lectin polymer lipid magnetic sphere prepared in this study was superparamagnetic and encapsulated by a lectin derivative. There was no significant difference in the recovery rate of AFP-L3 between avidin magnetic ball-automatic time-resolved fluorescence immunoassay and manual micro-affinity column method (p>0.05). We found that AFP-L3 can be used as a differential indicator between liver cancer and liver disease. The positive rate of AFP and AFP-L3 in liver cancer patients was higher than that in healthy people and liver disease patients (p<0.001). The AUC (95% CI) of AFP and AFP-L3 were 0.743 ± 0.031 and 0.850 ± 0.024, respectively. AFP-L3 AUC value is greater than AFP; therefore, AFP-L3 distinguishes liver cancer more accurately, and the difference is statistically different, p<0.05. We proposed a novel method for integration of the lectin polymer lipid magnetic spheres and time-resolved fluorescence immunoassay that enables simple, accurate and rapid determination of AFP-L3 in clinical samples. To be noted, fully automatic time-resolved fluorescence immunoassay compared with the commonly used techniques in clinical practice, the measurement procedure is simple and is expected to be used for the detection and accurate diagnosis of liver cancer.

Objective To characterize alpha‐fetoprotein (AFP)‐producing gastric cancer (AFPGC) at the single‐cell level and to identify regulatory factors for AFP expression and malignancy. Methods ScRNA‐seq was performed on two tumors collected from patients with AFPGC. InferCNV and sub‐clustering were applied to identify typical AFPGC cells, followed by AddModuleScore, pathway enrichment, Pseudo‐time, and Scenic analyses. Data from a gastric cancer (GC) cohort were collected for conjoint analysis. The analytical results were verified by cell experiments and immunohistochemistry. Results AFPGC cells are similar to hepatocytes in transcriptome and transcriptional regulation, with kinetic malignancy‐related pathways, compared to the common malignant epithelium. In addition, compared to common GC cells, malignancy‐related pathways, such as epithelial‐mesenchymal transition (EMT) and angiogenesis, were upregulated in AFPGC. Mechanistically, Dickkopf‐1 (DKK1) was found to be associated with AFP expression and malignant phenotype upon combining our scRNA‐seq data with a public database, which was further verified by a series of in vitro experiments and immunohistochemistry. Conclusion We demonstrated the single‐cell characteristics of AFPGC and that DKK1 facilitates AFP expression and malignancy. By applying single‐cell transcriptome sequencing to AFP‐producing gastric cancer (AFPGC), our study revealed novel molecular features of this rare disease. We also discovered a key gene, DKK1, that might regulate the malignant phenotype and AFP expression of AFPGC through a joint public database.

Chimeric antigen receptor (CAR)-T cell therapy targeting glypican-3 (GPC3) has shown promise in the treatment of hepatocellular carcinoma (HCC). However, the efficacy of CAR-T cells that focus solely on cell surface tumor-associated antigens is often limited. To overcome this challenge, we developed a dual-targeting CAR-T cell strategy. The intracellular alpha-fetoprotein (AFP) antigen, a well-established biomarker of liver cancer, presents the immunogenic Human Leukocyte Antigen (HLA)-A*02:01-restricted epitope 158–166. Consequently, we engineered a T cell receptor (TCR) mimic antibody with high specificity and affinity, providing a promising therapeutic avenue to target this critical antigen. To enhance treatment outcomes for liver cancer, we further modified previously developed GPC3 CAR-T cells, which demonstrated robust anti-tumor efficacy against GPC3-high tumor cells, to secrete an optimized bispecific T cell engager (BiTE) targeting the presented AFP antigen. This dual-targeting strategy significantly improved CAR-T cell proliferation and persistence, as well as enhancing cytokine expression and anti-tumor activity against HCC cells, particularly those exhibiting low GPC3 and AFP expression, both in vitro and in vivo. Our findings highlight the potential of this innovative approach to offer more effective treatment options for patients with liver cancer. Graphical sbstract

Liver cancers are common malignancies that primarily include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Currently, the most commonly used serum markers for HCC are alpha fetoprotein (AFP), AFP-L3% and protein induced by vitamin K absence or antagonist-II (PIVKA-II), while the most commonly used serum markers for CCA are carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). In recent years, many HCC diagnostic models using the combined detection of serum AFP, AFP-L3% and PIVKA-II have been established. For serum AFP, AFP-L3%, PIVKA-II and their many diagnostic models, there has been no clear guidance on the selection of these markers and their various combinations in the diagnosis of liver cancers. The aim of this study was to evaluate and compare the efficacy of these markers and the models that incorporate them in diagnosing HCC and CCA. This could assist in identifying the optimal patterns of serum AFP, AFP-L3% and PIVKA-II for the diagnosis of liver cancers. Clinical data and the results of serum AFP, AFP-L3%, PIVKA-II, CEA and CA19-9 were collected from 117 patients with HCC, 28 patients with CCA and 101 patients with benign liver diseases. Laboratory tests and detection of serum tumor markers in liver cancer patients were conducted prior to treatments. Recently published diagnostic models for AFP, AFP-L3% and PIVKA-II detection were collected; these included GALAD, ASAP, GALAD-C, GAAP, C-GALAD, C-GALAD II and GAP-TALAD. Levels of AFP-L3%, PIVKA-II, GALAD, ASAP, GALAD-C, GAAP, C-GALAD and C-GALAD II significantly differed between the patient cohorts, with the highest levels seen in HCC, followed by CCA and with the lowest levels seen in benign liver diseases ( < 0.05). Levels of CEA and CA19-9 significantly differed between cohorts, with the highest levels seen in CCA, followed by HCC and with the lowest levels seen in benign liver diseases ( < 0.05). Levels of AFP and GAP-TALAD in HCC patients were significantly higher than those in patients with CCA and patients with benign liver diseases ( < 0.05), but there were no significant differences in levels of AFP and GAP-TALAD between patients with CCA and benign liver diseases ( > 0.05). In the diagnosis of HCC, GAP-TALAD, GALAD, C-GALAD, ASAP and GALAD-C showed the highest efficacy. In the diagnosis of overall liver cancers (HCC and CCA), GALAD-C, GAAP, GALAD, ASAP and C-GALAD showed the highest efficacy. In the diagnosis of early liver cancers (early HCC and CCA), GALAD, GALAD-C, GAAP, C-GALAD and ASAP showed the highest efficacy. For serum AFP, AFP-L3% and PIVKA-II, diagnostic models of combined marker detection improved efficacy in the diagnosis of liver cancers. Diagnostic models GALAD, ASAP, GALAD-C and C-GALAD showed the highest efficacy in the diagnosis of HCC, overall liver cancers (HCC + CCA) and early liver cancers, and can be used preferentially in clinical practice.

Exosomal microRNAs have recently been studied as the potential diagnostic marker for various malignancies, including hepatocellular carcinoma (HCC). The aim of this study was to investigate serum exosomal microRNA profiles as HCC diagnostic marker. Transmission electron microscopy and Western blot were used to identify serum exosomes. Deep sequencing was performed to screen differentially expressed microRNAs between HCC (n = 5) and liver cirrhosis (LC, n = 5) groups. Three upregulated and two downregulated microRNAs were selected for qPCR analysis. The levels of selected microRNAs were normalized to Caenorhabditis elegans miR‐39 microRNA mimics. Serum exosomal level of miR‐122, miR‐148a, and miR‐1246 was further analyzed and significantly higher in HCC than LC and normal control (NC) groups (P < 0.001), but not different from chronic hepatitis group (P > 0.05). The receiver operating characteristic curve was used to evaluate the diagnostic performance of candidate microRNAs. Area under the curve (AUC) of miR‐148a was 0.891 [95% confidence interval (CI), 0.809–0.947] in discriminating HCC from LC, remarkably higher than alpha‐fetoprotein (AFP) (AUC: 0.712, 95% CI: 0.607–0.803). Binary logistic regression was adopted to establish the diagnostic model for discriminating HCC from LC. And the combination of miR‐122, miR‐148a, and AFP increased the AUC to 0.931 (95% CI, 0.857–0.973), which can also be applied for distinguishing early HCC from LC. miR‐122 was the best for differentiating HCC from NC (AUC: 0.990, 95% CI, 0.945–1.000). These data suggest that serum exosomal microRNAs signature or their combination with traditional biomarker may be used as a suitable peripheral screening tool for HCC. Significantly higher levels of serum exosomal miR‐122, miR‐148a, and miR‐1246 were found in subjects with hepatocellular carcinoma (HCC) than liver cirrhosis (LC) and normal control (NC). And the combination of exosomal microRNAs and alpha‐fetoprotein (AFP) yielded a better diagnostic power than AFP in discriminating subjects with (early) HCC from LC. Exosomal miR‐122 had the best diagnostic performance in discriminating HCC from NC subjects.

High serum alpha-fetoprotein (AFP) level is a predictor of poor prognosis in patients with gastric cancer (GC). AFP-producing GC (AFP-GC) is an aggressive subtype of GC characterized by a high incidence of liver metastasis and high c-Met expression. High expression of metastasis-associated colon cancer 1 (MACC1), which is the transcription activator of c-Met, also predicts a poor prognosis of GC. c-Met is known to be involved in tumor progression into malignant invasive phenotypes. Considering that high c-Met expression is simultaneously positively correlated with high AFP and MACC1 expression levels and that high expression of AFP or MACC1 predicts poor prognosis in GC, we hypothesized that an interaction may exist between AFP and MACC1. In the present study, GC cell lines with AFP-overexpression, MACC1-downregulation and the combination of both transfections were used as experimental models. The relative mRNA and protein expression of c-Met, AFP and MACC1 were analyzed using reverse transcription quantitative PCR and western blotting, respectively. Cell viability was evaluated using Cell Counting Kit-8 assay. Cell invasion and cell migration were examined using Transwell migration assay with and without Matrigel, respectively. The results demonstrated that, compared with the control group, the mRNA and protein expression of MACC1was significantly elevated in the AFP-overexpressed group and in the group with AFP overexpressed and MACC1 downregulated. Furthermore, a significantly enhanced cell viability, migration and invasion were observed in the AFP-overexpressing group, whereas opposite effects were found in the MACC1-downregulating group. In summary, the results from this study indicated that AFP may promote GC progression by stimulating MACC1. This finding may help illustrating the aggressive behaviors of GC in patients with high AFP serum level and AFP-GC.

Background/Objectives: Biomarkers such as lens agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin, as well as biomarker- and/or clinical-parameter-derived composite models (GALAD, GAAP, ASAP, aMAP, Doylestown), may improve detection in addition to alpha-fetoprotein, yet comparative data across diverse populations remain limited. Methods: In this biobank-based case–control study, we evaluated 562 adults (120 healthy controls, 277 chronic liver disease, 165 hepatocellular carcinoma) from January 2019 to 2024. Diagnostic performance for any-stage and early-stage hepatocellular carcinoma was assessed across three thresholds: Youden-index-derived optimal cut-offs, research-established cut-offs, and cut-offs ensuring 90% specificity. Receiver operating characteristic analysis was performed. Subgroup analyses were stratified by etiology and alpha-fetoprotein status. Results: At optimal cut-offs, GALAD showed the highest sensitivity for any-stage (90.3%) and early-stage (89.1%) hepatocellular carcinoma, with 70–80% specificity. Using established cut-offs, GALAD retained the highest sensitivity for any-stage (75.8%) and early-stage (57.8%) hepatocellular carcinoma, with 93.5% specificity. GALAD demonstrated the best performance in non-viral hepatocellular carcinomas (area under the curve 0.872), whereas GAAP and ASAP showed similarly high area under the curve values in viral etiology (area under the curve 0.955–0.960). Conclusions: Our results demonstrate the consistent performance of the GALAD score across diverse populations and underscore its superiority over individual biomarkers and other composite models. Notably, the GAAP and ASAP scores—which use one less biomarker (AFP-L3)—exhibited comparable performance, particularly in viral etiology. These findings support the integration of the composite biomarker models into tailored hepatocellular carcinoma surveillance strategies.

The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10–20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients’ survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.

Previous studies have found that alpha‐fetoprotein (AFP) can promote the proliferation of hepatoma cells and accelerate the progression of hepatocellular carcinoma (HCC). However, the exact mechanism of action remains unclear. Recent bioinformatics studies have predicted the possible interaction between AFP and retinoic acid receptors (RARs). Thus, the purpose of this study was to investigate the molecular mechanism through which AFP promotes tumour cell proliferation by interfering with the RA‐RAR signal pathway. Our data indicated that AFP could significantly promote the proliferation and weaken ATRA‐induced apoptosis of hepatoma cells. Besides, cytoplasmic AFP interacts with RAR, disrupting its entrance into the nucleus, which in turn affects the expression of the Bcl‐2 gene. In addition, knockdown of AFP in HepG2 cells was synchronously associated with an incremental increase of RAR binding to DNA, as well as down‐regulation of Bcl‐2; the opposite effect was observed in AFP gene‐transfected HLE cells. Moreover, a similar effect of AFP was detected in tumour tissues with high serum AFP, but not in adjacent non‐cancerous liver tissues, or HCC tissues with low serum AFP levels. These results indicate that AFP acts as signalling molecule and prevents RAR from entering into the nucleus by interacting with RAR, thereby promoting the expression of Bcl‐2. Our data reveal a novel mechanism through which AFP regulates Bcl‐2 expression and further suggest that AFP may be used as a novel target for treating HCC.