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Identifying the Prognostic Risk Factors of Synaptojanin 2 and Its Underlying Perturbations Pathways in Hepatocellular Carcinoma.

ABSTRACT: Synaptojanin 2 (SYNJ2) regulates cell proliferation and apoptosis via dephosphorylating plasma membrane phosphoinositides. Aim of this study is to first seek the full-scale expression levels and potential emerging roles of SYNJ2 in hepatocellular carcinoma (HCC). We systematically analyzed SYNJ2 mRNA expression and protein levels in HCC tissues based on large-scale data and in-house immunohistochemistry (IHC). The clinical significance and risk factors for SYNJ2-related HCC cases were identified. A nomogram of prognosis was created and its performance was validated by concordance index (C-index) and shown in calibration plots. Based on the identified differentially coexpressed genes (DCGs) of SYNJ2, enriched annotations and potential pathways were predicted, and the protein interacting networks were mapped. Upregulated SYNJ2 in 3,728 HCC and 3,203 non-HCC tissues were verified and in-house IHC showed higher protein levels of SYNJ2 in HCC tissues. Pathologic T stage was identified as a risk factor. Upregulated mRNA levels and mutated SYNJ2 might cause a poorer outcome. The C-index of the nomogram model constructed by SYNJ2 level, age, gender, TNM classification, grade, and stage was evaluated as 0.643 (95%CI = 0.619-0.668) with well-calibrated plots. A total of 2,533 DCGs were extracted and mainly functioned together with SYNJ2 in metabolic pathways. Possible transcriptional axis of CTCF/POLR2A-SYNJ2/INPP5B (transcription factor-target) in metabolic pathways was discovered based on ChIP-seq datasets. In summary, transcriptional regulatory axis CTCF/POLR2A-SYNJ2 might influence SYNJ2 expression levels. Increased SYNJ2 expression level could be utilized for predicting HCC prognosis and potentially accelerates the occurrence and development of HCC via metabolic perturbations pathways.

SUBMITTER: Zhang R

PROVIDER: S-EPMC8806346 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Several epithelial-mesenchymal transition (EMT)-associated genes (EAGs) have been confirmed to correlate with the prognosis of hepatocellular carcinoma (HCC) patients. Herein, we explored the value of EAGs in the prognosis of HCC relying on data from The Cancer Genome Atlas (TCGA) database. A total of 200 EMT-associated genes were downloaded from the Gene set enrichment analysis (GSEA) website. Moreover, 96 differentially expressed EAGs were identified. Using Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we forecasted the potential molecular mechanisms of EAGs. To identify prognostic EAGs, Cox regression was used in developing a prognostic risk model. Then, the Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to validate the prognostic significance of the model. A total of 5 prognostic correlated EAGs (P3H1, SPP1, MMP1, LGALS1, and ITGB5) were screened via Cox regression, which provided the basis for developing a novel prognostic risk model. Based on the risk model, patients were subdivided into high-risk and low-risk groups. The overall survival of the low-risk group was better compared to the high-risk group (P < 0.00001). The ROC curve of the risk model showed a higher AUC (Area under Curve) (AUC = 0.723) compared to other clinical features (AUC ≤ 0.511). A nomogram based on this model was constructed to predict the 1-year, 2-year, and 3-year overall survival rates (OS) of patients. Conclusively, we developed a novel HCC prognostic risk model based on the expression of EAGs, which help advance the prognostic management of HCC patients. Abbreviations: HCC: hepatocellular carcinoma; TCGA: The Cancer Genome Atlas; EMT: epithelial-mesenchymal transition; EAGs: EMT-associated genes; GSEA: gene set enrichment analysis; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: protein-protein interaction; TF: transcription factor; ROC: receiver operating characteristic; K-M: Kaplan-Meier; AUC: the area under the ROC curve; FDR: false discovery rate; TNM: Tumor size/lymph nodes/distance metastasis.

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Identifying the Prognostic Risk Factors of Synaptojanin 2 and Its Underlying Perturbations Pathways in Hepatocellular Carcinoma.

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