Dataset Information

The diagnostic and prognostic implications of PRKRA expression in HBV-related hepatocellular carcinoma.

ABSTRACT:

Background

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for more than half of total HCC patients in developing countries. Currently, HBV-related HCC diagnosis and prognosis still lack specific biomarkers. Here, we investigated if PRKRA expression in peripheral blood could be a potential biomarker for the diagnosis/prognosis of HBV-related HCC.

Methods

The expression of PRKRA in HBV-related HCC was firstly analyzed using TCGA and GEO databases. The results were confirmed in a validation cohort including 152 blood samples from 77 healthy controls and 75 HCC patients, 60 of which were infected with HBV. The potential diagnostic and prognostic values of PRKRA were also evaluated by the area under the receiver operator characteristic curve (AUROC) and Kaplan-Meier method, respectively.

Results

PRKRA was significantly upregulated in HCC patients, especially in those with HBV infections. In addition, the combination of PRKRA expression in peripheral blood with serum AFP and CEA levels displayed a better diagnostic performance (AUROC = 0.908, 95% CI 0.844-0.972; p < 0.001). Notably, when serum AFP is less than 200 ng/mL, PRKRA expression demonstrated better diagnostic capability. Furthermore, PRKRA expression levels were associated with expression of EIF2AK2 and inflammatory cytokine genes.

Conclusions

Triple combination testing of blood PRKRA expression, serum AFP and CEA levels could be a noninvasive strategy for diagnosis; and the elevation of PRKRA expression could predicate poor prognosis for HBV-related HCC.

SUBMITTER: Hu YM

PROVIDER: S-EPMC9211784 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

The diagnostic and prognostic implications of PRKRA expression in HBV-related hepatocellular carcinoma.

Hu Yi-Min YM Ran Ruoxi R Yang Chaoqi C Liu Song-Mei SM

Infectious agents and cancer 20220621 1

<h4>Background</h4>Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for more than half of total HCC patients in developing countries. Currently, HBV-related HCC diagnosis and prognosis still lack specific biomarkers. Here, we investigated if PRKRA expression in peripheral blood could be a potential biomarker for the diagnosis/prognosis of HBV-related HCC.<h4>Methods</h4>The expression of PRKRA in HBV-related HCC was firstly analyzed using TCGA and GEO databases. The result ...[more]

PMID: 35729579

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Project description:Background: Hepatocellular carcinoma (HCC) is a main cause of malignancy-related death all over the world with a poor prognosis. The current research is focused on developing novel prognostic and diagnostic models of Hepatocellular carcinoma from the perspective of hepatitis B virus (HBV)-related genes, and predicting its prognostic characteristics and potential reliable biomarkers for Hepatocellular carcinoma diagnosis. Methods: As per the information related to Hepatocellular carcinoma expression profile and the clinical data in multiple public databases, we utilized limma for assessing the differentially expressed genes (DEGs) in HBV vs non- hepatitis B virus groups, and the gene set was enriched, analyzed and annotated by WebGestaltR package. Then, STRING was employed to investigate the protein interactions. A risk model for evaluating Hepatocellular carcinoma prognosis was built with Lasso Cox regression analysis. The effect patients receiving immunotherapy was predicted using Tumor Immune Dysfunction and Exclusion (TIDE). Additionally, pRRophetic was used to investigate the drug sensitivity. Lastly, the Support Vector Machine (SVM) approach was utilized for building the diagnostic model. Results: The Hepatocellular Carcinoma Molecular Atlas 18 (HCCDB18) data set was utilized for the identification of 1344 HBV-related differentially expressed genes, mainly associated with cell division activities. Five functional modules were established and then we built a prognostic model in accordance with the protein-protein interaction (PPI) network. Five HBV-related genes affecting prognosis were identified for constructing a prognostic model. Then, the samples were assigned into RS-high and -low groups as per their relevant prognostic risk score (RS). High-risk group showed worse prognosis, higher mutation rate of TP53, lower sensitivity to immunotherapy but higher response to chemotherapeutic drugs than low-risk group. Finally, the hepatitis B virus diagnostic model of Hepatocellular carcinoma was established. Conclusion: In conclusion, the prognostic and diagnostic models of hepatitis B virus gene-related Hepatocellular carcinoma were constructed. ABCB6, IPO7, TIMM9, FZD7, and ACAT1, the five HBV-related genes that affect the prognosis, can work as reliable biomarkers for the diagnosis of Hepatocellular carcinoma, giving a new insight for improving the prognosis, diagnosis, and treatment outcomes of HBV-type Hepatocellular carcinoma.

Project description:Hepatocellular carcinoma (HCC) is a common malignant tumor that is characterized by aggressiveness and poor prognosis. Accumulating evidence indicates that oxidative stress plays a crucial role in carcinogenesis, whereas the potential mechanism between oxidative stress and carcinogenic effects remains elusive. In recent years, long noncoding RNAs (lncRNAs) in cancers have attracted extensive attention and have been shown to be involved in oxidative stress response and carcinogenesis. Nevertheless, the roles of lncRNA AL033381.2 in regulating the development and progression of HCC still remain unclear. The purpose of our study was to evaluate the potential effects and molecular mechanisms of AL033381.2 that may be involved in oxidative stress response in HCC. Using bioinformatics analyses based on the TCGA database, we screened and identified a novel lncRNA AL033381.2 in HCC, which may be involved in oxidative stress responses. qRT-PCR analysis revealed that AL033381.2 is upregulated in HCC tissues. Through in vitro and in vivo experiments, we found that AL033381.2 dramatically facilitates the growth and metastasis of HCC. Mechanistically, RNA pull-down experiments, mass spectrometry, PathArray™, and RIP were used to determine that AL033381.2 binds to PRKRA and may be involved in AL033381.2-mediated oncogenic functions in HCC cells. Moreover, rescue experiments demonstrated that PRKRA overexpression rescues the abilities of HCC cell proliferation, migration, and invasion that were affected by AL033381.2 knockdown. Furthermore, we produced a nanoparticle-based siRNA delivery system and tested its therapeutic effects in vivo. The results showed that the in vivo growth rate of the tumors treated with the nanoparticle/AL033381.2 siRNA complexes was dramatically lower than those treated with the nanoparticle/scramble siRNA complexes. Taken together, our results suggest that the novel lncRNA AL033381.2 may be involved in oxidative stress response by targeting oxidative stress-related genes in HCC. AL033381.2 plays vital oncogenic roles in HCC progression and may be a novel therapeutic marker for HCC diagnosis and treatment.

Project description:The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC.

Dataset Information

The diagnostic and prognostic implications of PRKRA expression in HBV-related hepatocellular carcinoma.

Background

Methods

Results

Conclusions

Publications

The diagnostic and prognostic implications of PRKRA expression in HBV-related hepatocellular carcinoma.

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