Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence with poor prognosis. Necroptosis is a kind of regulated cell death and has been proved to be of significance in cancer occurrence and progression. However, few studies comprehensively discuss the potential applications of necroptosis-related genes (NRGs) in the prognostic evaluation and immunotherapy of LIHC. The prognostic signature in the present study was built up using LASSO Cox regression analysis. Integrated bioinformatics tools were utilized to explore the potential mRNA-miRNA-lncRNA regulatory axis in LIHC. Furthermore, qRT-PCR method was used to verify the EZH2 expression in LIHC tissues. Furthermore, prognostic performance of EZH2 in LIHC was assessed by Kaplan-Meier method. A total of 14 NRGs were differentially expressed in LIHC tissues. The overall genetic mutation status of these NRGs in LIHC was also shown. NRGs were significantly correlated with programmed necrotic cell death, as well as Toll-like receptor signaling pathway in GO and KEGG pathway analysis. Kaplan-Meier analysis revealed that ALDH2, EZH2, NDRG2, PGAM5, RIPK1, and TRAF2 were related to the prognosis. A prognostic signature was constructed by these six genes and showed medium to high accuracy in the prediction of LIHC patients' prognosis. Further analysis revealed that NRGs were correlated with pathological stage, immune infiltration, and drug resistance in LIHC. Moreover, we identified a potential lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis in LIHC, which might affect the progression of LIHC. qRT-PCR suggested a higher mRNA level of EZH2 in LIHC tissues. And a poor overall survival rate was detected in LIHC patients with high EZH2 expression. Moreover, EZH2 expression and cancer stage were identified as the independent risk factors affecting LIHC patients' prognosis. In the present study, we conducted comprehensive bioinformatic analyses and built up a necroptosis-related prognostic signature containing four genes (ALDH2, EZH2, NDRG2, and PGAM5) for patients with LIHC, and this prognostic signature showed a medium to high predictive accuracy. And our study also identified a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might be of great significance in LIHC progression. In addition, based on the data from our center, the result of qRT-PCR and survival analysis showed a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively.

He A ，Huang Z ，Wang J ，Lu H ，Zhang R ，Wu L ，Feng Q ... -  《-》

Identification and Validation a Necroptosis‑related Prognostic Signature and Associated Regulatory Axis in Stomach Adenocarcinoma.

Gastric cancer (GC) ranks fifth in global cancer incidence and third in cancer-related mortality. The prognosis of GC patients was poor. Necroptosis is a type of regulated cell death mediated by RIP1, RIP3, and MLKL. Necroptosis was found to be involved in antitumor immunity in the cancer immunotherapy. LASSO Cox regression analysis was performed to construct a prognostic signature. Bioinformatics analysis was performed to construct a lncRNA-miRNA-mRNA regulatory axis. qRT-PCR was performed to verify the expression and prognosis of hub gene in STAD. Most of necroptosis regulators were upregulated, while the mRNA level of TLR3, ALDH2, and NDRG2 was downregulated in STAD versus gastric tissues. The genetic mutation and copy number variation of necroptosis regulator in STAD were also summarized. GO and KEGG pathways analysis revealed that these necroptosis regulators were mainly involved in programmed necrotic cell death and TNF signaling pathway. A necroptosis‑related prognostic signature based on four genes (EZH2, PGAM5, TLR4, and TRAF2) had a good performance in predicting the prognosis of STAD patients. We also identified lncRNA SNHG1/miR-21-5p/TLR4 regulatory axis in the progression in STAD. Verification study suggested that the hub gene TLR4 upregulated in STAD and correlated with a poor overall survival. Moreover, Cox regression analysis revealed that TLR4 expression and clinical stage were independent factors affecting the prognosis of STAD patients. We performed a comprehensive bioinformatics analysis and identified a necroptosis‑related prognostic signature and a lncRNA SNHG1/miR-21-5p/TLR4 regulatory axis in STAD. Further study should be performed to confirm our result.

Wang N ，Liu D 《OncoTargets and Therapy》

Construction of liver hepatocellular carcinoma-specific lncRNA-miRNA-mRNA network based on bioinformatics analysis.

Wang R ，Hu X ，Liu X ，Bai L ，Gu J ，Li Q ... -  《PLoS One》

Development and validation of multi-omic prognostic signature of anoikis-related genes in liver hepatocellular carcinoma.

Liver hepatocellular carcinoma (LIHC) is characterized by high morbidity, rapid progression and early metastasis. Although many efforts have been made to improve the prognosis of LIHC, the situation is still dismal. Inability to initiate anoikis process is closely associated with cancer proliferation and metastasis, affecting patients' prognosis. In this study, a corresponding gene signature was constructed to comprehensively assess the prognostic value of anoikis-related genes (ARGs) in LIHC. Using TCGA-LIHC dataset, the mRNA levels of the differentially expressed ARGs in LIHC and normal tissues were compared by Student t test. And prognostic ARGs were identified through Cox regression analysis. Prognostic signature was established and then externally verified by ICGC-LIRI-JP dataset and GES14520 dataset via LASSO Cox regression model. Potential functions and mechanisms of ARGs in LIHC were evaluated by functional enrichment analyses. And the immune infiltration status in prognostic signature was analyzed by ESTIMATE algorithm and ssGSEA algorithm. Furthermore, ARGs expression in LIHC tissues was validated via qRT-PCR and IHC staining from the HPA website. A total of 97 differentially expressed ARGs were detected in LIHC tissues. Functional enrichment analysis revealed these genes were mainly involved in MAP kinase activity, apoptotic signaling pathway, anoikis and PI3K-Akt signaling pathway. Afterward, the prognostic signature consisting of BSG, ETV4, EZH2, NQO1, PLK1, PBK, and SPP1 had a moderate to high predictive accuracy and served as an independent prognostic indicator for LIHC. The prognostic signature was also applicable to patients with distinct clinical parameters in subgroup survival analysis. And it could reflect the specific immune microenvironment in LIHC, which indicated high-risk group tended to profit from ICI treatment. Moreover, qRT-PCR and IHC staining showed increasing expression of BSG, ETV4, EZH2, NQO1, PLK1, PBK and SPP1in LIHC tissues, which were consistent to the results from TCGA database. The current study developed a novel prognostic signature comprising of 7 ARGs, which could stratify the risk and effectively predict the prognosis of LIHC patients. Furthermore, it also offered a potential indicator for immunotherapy of LIHC.

Ding D ，Wang D ，Qin Y 《-》

A Pyroptosis-Related Gene Signature to Predict Patients' Prognosis and Immune Landscape in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) is a malignance with high incidence and recurrence. Pyroptosis is a programed cell death pattern which both activates the effective immune response and causes cell damage. However, their potential applications of pyroptosis-related genes (PRGs) in the prognostic evaluation and immunotherapy of LIHC are still rarely discussed. Comprehensive bioinformatics analyses based on TCGA-LIHC dataset were performed in the current study. A total of 33 PRGs were selected to perform the current study. Of these 33 PRGs, 26 PRGs with upregulation or downregulation in LIHC tissues were identified. We also summarized the related genetic mutation variation landscape. GO and KEGG pathway analysis demonstrated that these 26 PRGs were primarily associated with pyroptosis, positive regulation of interleukin-1 beta production, and NOD-like receptor signaling pathway. An unfavorable OS appeared in LIHC patients with high CASP3, CASP4, CASP6, CASP8, GPX4, GSDMA, GSDME, NLRP3, NLRP7, NOD1, NOD2, PLCG1, and SCAF11 expression and low NLRP6 expression. A prognostic signature constructed by the above 14 prognostic PRGs had moderate to high accuracy to predict LIHC patients' prognosis. And risk score was correlated with the expression of CASP6, CASP8, GPX4, GSDMA, GSDME, NLRP6, and NOD2. Of these 7 genes, CASP8 was identified as the core gene in PPI network. Moreover, lncRNA MIR17HG/hsa-miRNA-130b-3p/CASP8 regulatory axis in LIHC was also detected. The current study indicated the crucial role of PRGs in the prognostic evaluation of LIHC patients and their correlations with tumor microenvironment in LIHC.

Wang J ，Huang Z ，Lu H ，Zhang R ，Feng Q ，He A ... -  《-》