Prognostic Lysosome-Related Biomarkers for Predicting Drug Candidates in Hepatocellular Carcinoma: An Insilco Analysis.

BACKGROUND

Lysosomes play an important role in enhancing tumorigenesis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, a detailed analysis of the role of lysosome-related genes could improve the poor prognosis of HCC patients.

METHODS

Lysosome-associated genes were downloaded from the GO and Genome Enrichment Analysis (GSEA) databases. After analyzing lysosome-associated differentially expressed genes (DEGs) between the TCGA and GTEx cohorts, we used univariate Cox regression, LASSO-Cox regression, stepwise Cox regression, and multivariate Cox regression analyses to build a predictive risk model. The ICGC cohort was used as a test cohort for the prognostic signature's validation. It was also assessed how significantly the signature affected the tumor microenvironment (TME) and sensitivity to immune checkpoint inhibitors. To investigate the expression of this signature in clinical samples, qRT-PCR and immunohistochemistry (IHC) were carried out in 50 normal tissues and 59 HCC tissues.

RESULTS

A total of 894 lysosome-associated genes were obtained. After identifying 113 lysosome-associated DEGs, we constructed a five-gene prognostic signature (RRAGD, AP1M2, CRHBP, NCSTN, and SLCO4C1) that can be effectively applied to the prognostic classification of HCC patients in TCGA and ICGC cohorts. Additionally, we discovered that this signature can affect the proportion of macrophage infiltration in TME. We also evaluated several tumor-sensitive medicines that affect this signature. Finally, we discovered that HCC tissues had lower amounts of CRHBP compared to normal tissues by the qRT-PCR and IHC assay.

CONCLUSION

We developed and validated a predictive signature of five lysosome-related genes for HCC patients and verified the downregulation of CRHBP expression in clinical samples, which may provide fresh perspectives for customized immunotherapy.