Integrative genomic and transcriptomic profiling identifies HSPA5 as a central player in hepatocellular carcinoma pathogenesis.

It is known that Hepatocellular carcinoma (HCC) accounts for the highest number of deaths due to primary liver cancer and is one of the leading global oncology cases. Currently, in spite of many other efforts to improve the treatment, the prognosis is rather poor with HCC patients, indicating the necessity of new biomarkers and therapeutic targets. In this study, we undertook a multi-omics approach including exome sequencing, GO analysis, PPI network analysis, bulk RNA-seq, single-cell RNA-seq, spatial transcriptomics, and Venn and survival analysis to search decisively for drivers of liver cancer. Our investigation focused on revealing particular somatic mutations in genes implicated in various fundamental processes of cellular biology. In view of this barrier, we were then able to single out FN1, JUN, H3C12, HSPA5, and FOS among all components at the molecular landscape of HCC, where the levels of expression in turn related to patient survival. The formal HSPA5 (Heat Shock Protein Family A Member 5) gene is a molecular chaperone participates in the unfolded protein response and transcriptional endoplasmic reticulum stress, which was highly elevated in HCC tissues. Bulk RNA-seq confirmed the overexpression of HSPA5, while single-cell RNA-seq showed the higher expression of this protein in some populations of tumor cells attesting to its importance during HCC progression at a cellular level. Meanwhile, spatial transcriptomics reinforced these results with more precise data, showing where inside the tumor microenvironment HSPA5 is highlighted. In addition, PPI analysis showed much interaction of the proteins identified, bringing emphasis on their functions in HCC. Increased HSPA5 expression levels are linked with low overall survival rates and so it raised the prospect of being a diagnostic tool. Thus, HSPA5 shows promise as a cancer biomarker as well as a target therapeutic agent for HCC and hence detailed studies on its role in liver cancer and application in precision medicine for better outcome of patients need to be carried out.