Abstract
Objective: Emerging evidence highlights the implications of the toll-like receptor (TLR) signaling pathway in the pathogenesis and therapeutic regimens of hepatocellular carcinoma (HCC). Herein, a prognostic TLR-based gene signature was conducted for HCC.Methods: HCC-specific TLRs were screened in the TCGA cohort. A LASSO model was constructed based on prognosis-related HCC-specific TLRs. The predictive efficacy, sensitivity, and independency of this signature was then evaluated and externally verified in the ICGC, GSE14520, and GSE76427 cohorts. The associations between this signature and tumor microenvironment (stromal/immune score, immune checkpoint expression, and immune cell infiltrations) and chemotherapy response were assessed in HCC specimens. The expression of TLRs in this signature was verified in HCC and normal liver tissues by Western blot. Following si-MAP2K2 transfection, colony formation and apoptosis of Huh7 and HepG2 cells were examined.Results: Herein, we identified 60 HCC-specific TLRs. A TLR-based gene signature (MAP2K2, IRAK1, RAC1, TRAF3, MAP3K7, and SPP1) was conducted for HCC prognosis. High-risk patients exhibited undesirable outcomes. ROC curves confirmed the well prediction performance of this signature. Multivariate Cox regression analysis demonstrated that the signature was an independent prognostic indicator. Also, high-risk HCC was characterized by an increased immune score, immune checkpoint expression, and immune cell infiltration. Meanwhile, high-risk patients displayed higher sensitivity to gemcitabine and cisplatin. The dysregulation of TLRs in the signature was confirmed in HCC. MAP2K2 knockdown weakened colony formation and elevated apoptosis of Huh7 and HepG2 cells.Conclusion: Collectively, this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients.
Highlights
Hepatocellular carcinoma (HCC) represents the most frequent visceral neoplasm, occupying 70–90% of all primary liver cancer (Craig et al, 2020).Currently, surgery, transplantation, and percutaneous ablations have become major therapeutic strategies against HCC (Piñero et al, 2020; Yang et al, 2020)
With the |log2 foldchange|>2 and adjusted p < 0.05, we identified 60 HCC-specific Toll-like receptors (TLRs) (Table 1)
14 TLRs were downregulated, while 46 were upregulated in the HCC tissues in comparison with the normal tissues (Figures 1A,B). This indicated that dysregulation of these TLRs might contribute to HCC progression
Summary
Hepatocellular carcinoma (HCC) represents the most frequent visceral neoplasm, occupying 70–90% of all primary liver cancer (Craig et al, 2020).Currently, surgery, transplantation, and percutaneous ablations have become major therapeutic strategies against HCC (Piñero et al, 2020; Yang et al, 2020). Hepatitis B and C viral infections are the main risk factors of HCC (Sagnelli et al, 2020). This neoplasm is characterized by complex heterogeneity and high recurrence (Yang and Heimbach, 2020). This study screened HCC-specific TLRs as well as developed and externally verified a TLR-based gene signature for HCC. This signature enabled predicting survival outcomes and was in relation to tumor microenvironment (TME) and responses to chemotherapy drugs gemcitabine and cisplatin.
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