Significant correlation between HSPA4 and prognosis and immune regulation in hepatocellular carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) is an inflammation-associated tumor involved in immune tolerance and evasion in the immune microenvironment. Heat shock proteins (HSPs) are involved in the occurrence, progression, and immune regulation of tumors. Therefore, HSPs have been considered potential therapeutic targets. Here, we aimed to elucidate the value of HSP family A (Hsp70) member 4 (HSPA4) in the diagnosis and predicting prognosis of HCC, and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints. Gene mutation, DNA methylation, and the pathway involved in HCC were also analyzed. Methods The gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to compare HSPA4 expression, and the results were confirmed by immunohistochemical staining of clinical samples. R package was used to analyze the correlation between HSPA4 and cancer stage, and to establish receiver operating characteristic (ROC) curve of diagnosis, time-dependent survival ROC curve, and a nomogram model. cBioPortal and MethSurv were used to identify genetic alterations and DNA methylation, and their effect on prognosis. The Tumor Immune Estimation Resource (TIMER) was used to analyze immune cell infiltration, immune cell biomarkers, and immune checkpoints. The STRING database was used to analyze protein–protein interaction network information. Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functions of HSPA4 and its functional partner genes. Results Overexpression of HSPA4 was identified in 25 cancers. Overexpression of HSPA4 considerably correlated with cancer stage and alpha-fetoprotein (AFP) level in HCC. Patients with higher HSPA4 expression showed poorer prognosis. HSPA4 expression can accurately identify tumor from normal tissue (AUC = 0.957). The area under 1-, 3-, and 5-year survival ROCs were above 0.6. The HSPA4 genetic alteration rate was 1.3%. Among the 14 DNA methylation CpG sites, seven were related to the prognosis of HCC. HSPA4 was positively related to immune cell infiltration and immune checkpoints (PD-1 and CTLA-4) in HCC. The KEGG pathway enrichment analysis revealed HSPA4 enrichment in antigen processing and presentation together with HSPA8 and HSP90AA1. We verified the value of HSPA4 in the diagnosis and predicting prognosis of HCC. HSPA4 may not only participate in the occurrence and progression but also the immune regulation of HCC. Therefore, HSPA4 can be a potential diagnostic and prognostic biomarker and a therapeutic target for HCC.

INK4 cyclin-dependent kinase inhibitors as potential prognostic biomarkers and therapeutic targets in hepatocellular carcinoma

“…Jiang et al found that cell-cycle activity was associated with antitumor immunity in ten TCGA cancer cohorts, including HCC, and identified that the expression of many cell-cycle pathway genes was positively correlated with antitumor immunity [ 40 ]. The efficacy of immunotherapy requires sufficient immune infiltration into the tumor microenvironment and depends on the expression of immune checkpoint molecules [ 41 , 42 ]. Recent studies have reported that CDKN2A is closely associated with immune infiltration of HCC [ 12 , 43 , 44 ].…”

Differential Expression Profiles of mRNA and Noncoding RNA and Analysis of Competitive Endogenous RNA Regulatory Networks in Nonalcoholic Steatohepatitis

“…Other studies have shown that HSPA4 is significantly correlated with the prognosis and immune regulation of HCC. Therefore, HSPA4 might be a potential diagnostic and prognostic biomarker as well as a therapeutic target for HCC [ 20 ]. In previous studies, these genes, including both MAPK1 and HSPA4, were not reported to be related to NASH but other liver-related diseases.…”

Characterization of Necroptosis-Related Molecular Subtypes and Therapeutic Response in Lung Adenocarcinoma

“…In vitro , Tan et al (2020 ) further demonstrated that the activation of RIP3/MLKL-dependent necroptosis could increase the therapeutic sensitivity to gefitinib in NSCLC patients. Heat-shock protein family A (Hsp70) member 4 (HSPA4) was involved in the functional stabilization of mutated or aberrantly expressed genes in multiple tumors ( Lv et al, 2012 ) and had been identified to have a significant correlation with immune regulation and prognosis of hepatocellular carcinoma ( Shang et al, 2021 ). Notably, as the sole protective NRG for LUAD, CYLD Lysine 63 Deubiquitinase (CYLD) had been considered as the tumor suppressor and further demonstrated to be regulated by miR-96-5p and LncRNA GMDS-AS1 to inhibit the development of LUAD via a cellular assay and mouse tumor models ( Zhao et al, 2020 ).…”