Construction and validation of a novel lysosomal signature for hepatocellular carcinoma prognosis, diagnosis, and therapeutic decision-making.

Lysosomes is a well-recognized oncogenic driver and chemoresistance across variable cancer types, and has been associated with tumor invasiveness, metastasis, and poor prognosis. However, the significance of lysosomes in hepatocellular carcinoma (HCC) is not well understood. Lysosomes-related genes (LRGs) were downloaded from Genome Enrichment Analysis (GSEA) databases. Lysosome-related risk score (LRRS), including eight LRGs, was constructed via expression difference analysis (DEGs), univariate and LASSO-penalized Cox regression algorithm based on the TCGA cohort, while the ICGC cohort was obtained for signature validation. Based on GSE149614 Single-cell RNA sequencing data, model gene expression and liver tumor niche were further analyzed. Moreover, the functional enrichments, tumor microenvironment (TME), and genomic variation landscape between LRRSlow/LRRShigh subgroup were systematically investigated. A total of 15 Lysosomes-related differentially expressed genes (DELRGs) in HCC were detected, and then 10 prognosis DELRGs were screened out. Finally, the 8 optimal DELRGs (CLN3, GBA, CTSA, BSG, APLN, SORT1, ANXA2, and LAPTM4B) were selected to construct the LRRS prognosis signature of HCC. LRRS was considered as an independent prognostic factor and was associated with advanced clinicopathological features. LRRS also proved to be a potential marker for HCC diagnosis, especially for early-stage HCC. Then, a nomogram integrating the LRRS and clinical parameters was set up displaying great prognostic predictive performance. Moreover, patients with high LRRS showed higher tumor stemness, higher heterogeneity, and higher genomic alteration status than those in the low LRRS group and enriched in metabolism-related pathways, suggesting its underlying role in the progression and development of liver cancer. Meanwhile, the LRRS can affect the proportion of immunosuppressive cell infiltration, making it a vital immunosuppressive factor in the tumor microenvironment. Additionally, HCC patients with low LRRS were more sensitive to immunotherapy, while patients in the high LRRS group responded better to chemotherapy. Upon single-cell RNA sequencing, CLN3, GBA, and LAPTM4B were found to be specially expressed in hepatocytes, where they promoted cell progression. Finally, RT-qPCR and external datasets confirmed the mRNA expression levels of model genes. This study provided a direct links between LRRS signature and clinical characteristics, tumor microenvironment, and clinical drug-response, highlighting the critical role of lysosome in the development and treatment resistance of liver cancer, providing valuable insights into the prognosis prediction and treatment response of HCC, thereby providing valuable insights into prognostic prediction, early diagnosis, and therapeutic response of HCC.

Construction and validation of a novel IGFBP3-related signature to predict prognosis and therapeutic decision making for Hepatocellular Carcinoma.

Background: IGFBP3 plays a pivotal role in carcinogenesis by being anomalously expressed in some malignancies. However, the clinical value of IGFBP3 and the role of IGFBP3-related signature in HCC remain unclear. Methods: Multiple bioinformatics methods were used to determine the expression and diagnostic values of IGFBP3. The expression level of IGFBP3 was validated by RT-qPCR and IHC. A IGFBP3-related risk score (IGRS) was built via correlation analysis and LASSO Cox regression analysis. Further analyses, including functional enrichment, immune status of risk groups were analyzed, and the role of IGRS in guiding clinical treatment was also evaluated. Results: IGFBP3 expression was significantly downregulated in HCC. IGFBP3 expression correlated with multiple clinicopathological characteristics and demonstrated a powerful diagnostic capability for HCC. In addition, a novel IGRS signature was developed in TCGA, which exhibited good performance for prognosis prediction and its role was further validated in GSE14520. In TCGA and GSE14520, Cox analysis also confirmed that the IGRS could serve as an independent prognostic factor for HCC. Moreover, a nomogram with good accuracy for predicting the survival of HCC was further formulated. Additionally, enrichment analysis showed that the high-IGRS group was enriched in cancer-related pathways and immune-related pathways. Additionally, patients with high IGRS exhibited an immunosuppressive phenotype. Therefore, patients with low IGRS scores may benefit from immunotherapy. Conclusions: IGFBP3 can act as a new diagnostic factor for HCC. IGRS signature represents a valuable predictive tool in the prognosis prediction and therapeutic decision making for Hepatocellular Carcinoma.