Biomarker Research最新文献

Background: While miR-22 is a suppressor of hepatocellular carcinoma (HCC), galectin-1 (Gal-1) serves as a HCC biomarker. Our previous studies have shown the effectiveness of miR-22 gene therapy and silencing Gal-1 as two potential novel options in treating HCC in preclinical mouse models. This study examines the significance of the miR-22-Gal-1 axis in HCC development and treatment.

Methods: The roles of miR-22 and Gal-1 in human HCC were analyzed using the Cancer Genome Atlas database based on their expression levels. The temporal effects of miR-22 were studied by analyzing signaling pathways affected by miR-22 expression levels during HCC progression. AAV8-miR-22, AAV9-Gal-1 siRNA, and LLS30, a Gal-1 inhibitor, were used to treat orthotopic mouse HCC. Spatial transcriptomics established the location-specific effects of miR-22 in mouse HCC. The signaling pathways affected by miR-22 and Gal-1 were identified by analyzing human HCC transcriptomics compared with those found in miR-22, Gal-1 siRNA, or LLS30-treated mouse HCC.

Results: In the early stages of HCC, miR-22-high HCC exhibited extensive upregulation of endobiotic metabolism and xenobiotic detoxification signaling, accompanied by the activation of complement and clotting cascades. In late HCC stages, miR-22-high HCC exhibited heightened innate and adaptive immunity, associated with increased interferon signaling. These impacts were primarily observed in the tumors. At the tumor margin, miR-22 inhibited the Rho GTPase and cell-matrix interaction, revealing its role in reducing matrix remodeling and mobility. In non-tumor areas, miR-22 inhibited inflammation by reducing neutrophil degranulation, platelet activation, chemokine receptor binding, and fiber formation. miR-22, Gal-1 silencing, and LLS30 each exhibited anti-HCC effects and targeted common intracellular signaling pathways. Moreover, the anti-HCC effect of miR-22 was dependent on Gal-1 silencing. miR-22-high/Gal-1-low HCC patients had the best survival outcomes. In addition to the above-mentioned key intracellular pathways, miR-22 gene therapy and Gal-1 siRNA treatment of HCC reduced O-linked glycosylation, suggesting the role of the miR-22-Gal-1 axis in modifying glycosylation, which may affect the extracellular functions of Gal-1.

Conclusion: In summary, the miR-22-Gal-1 axis can be an HCC prognostic biomarker, and it has vital roles in regulating metabolism and tumor immunity.

Classical Hodgkin lymphoma (cHL) is a heterogeneous malignancy with favorable outcomes, but accurate prognostic stratification remains challenging, particularly across all disease stages. Traditional risk models are focused on advanced stages and do not account for tumor microenvironment (TME) dynamics. Soluble cytokines reflecting TME activity may offer additional prognostic value. In our prospective multicenter study, we investigated the prognostic value of pretreatment plasma levels of soluble TARC, sCD30, sCD163, and sIL-6 in 162 newly diagnosed cHL patients and developed a model incorporating these biomarkers for risk prediction across all stages. Cytokine levels were measured using ELISA, and clinical characteristics, treatment responses, and outcomes were collected. The primary endpoint was 5-year progression-free survival (PFS). Elevated levels of sIL-6 and sCD30 were associated with higher disease stage, presence of B-symptoms, extranodal involvement, and inferior 5-year PFS. A novel prognostic model incorporating age, extranodal disease, and high sCD30/sIL-6 levels outperformed IPS-3 in predicting therapy failure. Patients with both elevated sCD30 and sIL-6 levels at diagnosis had significantly worse outcomes. Integrating soluble cytokine biomarkers, particularly sIL-6 and sCD30, into prognostic models enhances risk stratification across all stages of cHL and supports future efforts toward biomarker-driven, personalized treatment strategies.

Remodeling of the tumor microenvironment (TME) under therapeutic pressure is a critical determinant of treatment response and resistance in hepatocellular carcinoma (HCC). Triple-combination therapy integrating targeted agents, immune checkpoint inhibitors, and radiotherapy (T+I+R) has shown potential synergistic effects in intermediate to advanced HCC, particularly in patients with portal vein tumor thrombus (PVTT), yet the spatial and cellular mechanisms underlying its efficacy remain largely unknown. In this retrospective clinical cohort study, we compared T+I+R with targeted therapy plus radiotherapy (T+R) in advanced HCC, and further employed single-cell spatial transcriptomics and spatial proteomics to generate an integrated multi-omics atlas mapping tumor and stromal compartments, cellular compositions, and intercellular interactions with spatial resolution. Clinically, T+I+R achieved superior tumor shrinkage and disease control compared with T+R. Spatial multi-omics revealed marked region-specific remodeling, with myofibroblastic cancer-associated fibroblasts, angiogenic tip endothelial cells, and conventional dendritic cells enriched at the invasive margin and associated with therapeutic resistance, while CD8⁺ effector T cells were redistributed away from immunosuppressive niches, a spatial configuration correlating with enhanced response. These findings identify spatial segregation between cytotoxic and suppressive immune elements as a potential hallmark of effective therapy, providing a high-resolution spatial framework for understanding T+I+R induced TME remodeling and offering mechanistic insights to guide biomarker discovery and the optimization of combination strategies in advanced HCC.

The mechanisms by which prostate cancer (PCa) evades anti-tumor immunity and the immune checkpoint blockade (ICB) response are poorly understood. Yes-associated protein 1 (YAP1) activation is a common feature in PCa. However, to date, there is no direct evidence regarding the effect of YAP1 activity on anti-tumor immunity in PCa patients. In this study, we discovered that YAP1 expression is usually abundant in PCa tissues. Transcriptome analysis revealed that PD-L1 and the immune costimulatory molecule CD70 were consistently upregulated in YAP1-activated PCa cells. Meanwhile, CD70 is also abundantly exhibited in ICB non-responder patients, but absent in ICB responders, who usually show high cytotoxic T cell infiltration. More importantly, CD70 inhibition restores the sensitivity to anti-PD-1 immunotherapy in YAP1-activated PCa cells. Mechanistically, YAP1 directly regulates the transcription of CD70 through cooperation with DNA-binding factor RUNX1. The upregulation of CD70 thus suppresses immune cell infiltration into malignant lesions and promotes the exhaustion of CD8 + T cells to facilitate evasion from immunosurveillance. Taken together, our findings define the YAP1-CD70 signaling axis as a novel immunosuppressive mechanism in PCa, which provides new insights into the potential of targeting the CD70 pathway to help further subdivide the population of PCa patients who can benefit from immunotherapy.