Predictive Models for HCC Prognosis, Recurrence Risk, and Immune Infiltration Based on Two Exosomal Genes: MYL6B and THOC2

Abstract

Introduction: Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC. Objective: The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis. Methods: Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2. Results: The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P<0.001), the ICGC cohort (HR=3.15, P<0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P<0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P<0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules. Conclusion: Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.

Comprehensive Analysis of the Expression and Clinical Significance of THO Complex Members in Hepatocellular Carcinoma

“…Low-expression THOC2 patients had higher sensitivity to chemotherapy. 17 In addition, recent experiments had confirmed that THOC4 is the drug target of neuroblastoma. 43 Therefore, the research of THO complex members in the direction of targeted treatment of HCC has great potential and further research is very necessary.…”

“…The expression levels of the immune checkpoints including PD1 and CTLA4 were positively correlated with THOC2 expression in HCC, which had a significant function in regulating the activation of T cells. 17 THOC4, one of the components of T cell enhanceosome, was involved in T cell maturation and provided the molecular basis for the expression of MHC class I genes. 50 As a cytoplasmic substrate for Fms tyrosine kinase activated by macrophage colony-stimulating factor, THOC5 was directly involved in the differentiation of macrophages.…”

“…Reports showed that the inhibition of THOC1 and THOC2 could inhibit the proliferation and migration of HCC cells. 16 , 17 He et al reported that THOC4 regulated 5-methylcytosine (m5C) methylation modifications in HCC and had diagnostic value. 18 Saran et al reported that the expression of THOC5 was increased by 78% in HCC cells with cytological differentiation grading G2 and G3 tumor.…”

Current Perspectives on the Unique Roles of Exosomes in Drug Resistance of Hepatocellular Carcinoma

“…Kim et al 85 believed that exosomal miR-125b may be a reliable biomarker for the diagnosis and evaluation of extrahepatic metastasis of HCC. Zhu et al 91 established a prognosis and recurrence risk prediction model, which presented a significant predictive performance, based on two exosomal genes (MYL6B and THOC2). These findings provide a foundation for improving the early detection of HCC via identifying molecular markers.…”

Immune-Related lncRNA Pairs Clinical Prognosis Model Construction for Hepatocellular Carcinoma

“…6,7 Immunotherapy that activates tumor-specific immune response has brought new hope for the treatment of HCC. 8 The liver is the largest immune organ in the body, rich in a variety of immune cells. 9 HCC tumor immune microenvironment is extremely complex, which is composed of cross-linking between tumor components (such as cancer cells, stromal cells and immune cells).…”