Identification, Verification and Pathway Enrichment Analysis of Prognosis-Related Immune Genes in Patients With Hepatocellular Carcinoma

Zhu, Zhipeng; Song, Mengyu; Li, Wenhao; Li, Mengying; Chen, Sihan; Chen, Bin

doi:10.3389/fonc.2021.695001

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…In HCC, NR6A1 was identified as a prognostic marker, and associated with sorafenib resistance in HCC patients 27 . Lin et al showed that NR6A1 might inhibit the HCC immune response 28 and activate the WNT signaling pathway as well as MTOR-signaling pathway 29 , which were similar to our study. On the other hand, NR6A1 could enhance HCC proliferation and invasion in vitro and vivo 29 , which indicated that NR6A1 showed promise as a novel immune therapeutic target for HCC.…”

Section: Discussionsupporting

confidence: 92%

Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma

Wu,

Li,

Long

et al. 2023

Sci Rep

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Histone lysine lactylation (Kla) plays a vital role in the tumorigenesis of hepatocellular carcinoma (HCC). Hence, we focused on Kla-specific genes to select novel therapeutic targets. Differentially expressed Kla-specific genes (DEKlaGs) were identified from TCGA with the cut-off criteria |log2(FlodChange (FC))| > 2, p-value < 0.05, following investigating the prognostic value. The correlation between lactate accumulation and prognostic DEKlaGs expression was further investigated. On the other hand, we explored the roles of Kla activation in the immune microenvironment, immunotherapy, and drug resistance. We conducted gene set enrichment analysis (GSEA) to predict the pathways influenced by Kla. The predictive power of Cox model was further identified in ICGC and GEO databases. A total of 129 DEKlaGs were identified, and 32 molecules might be potential prognostic biomarkers. A Cox model including ARHGEF37, MTFR2, NR6A1, NT5DC2, OSBP2, RNASEH2A, SFN, and UNC119B was constructed, which suggested unfavorable overall survival in high-risk score group, and risk score could serve as an indicator for large tumor size, poor pathological grade and advanced stage. NR6A1, OSBP2 and UNC119B could inhibit NK cell as well as TIL cell infiltration, and impair Type-I and II IFN responses in HCC, thereby contributing to unsatisfactory prognosis and immunotherapy resistance. OSBP2 and UNC119B were identified to be related to chemotherapy resistance. GSEA showed that WNT, MTOR, MAPK and NOTCH signaling pathways were activated, indicating that these pathways might play a crucial role during the Kla process. On the other hand, we showed that NR6A1 and OSBP2 were overexpressed in GEO. OSBP2 and UNC119B contributed to poor survival and advanced stage in ICGC. In summary, histone Kla was related to HCC prognosis and might serve as an independent biomarker. NR6A1, OSBP2 and UNC119B were associated with the prognosis, immunotherapy, and chemotherapy resistance, suggesting that NR6A1, OSBP2 and UNC119B might be novel candidate therapeutic targets for HCC.

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Section: Discussionsupporting

confidence: 92%

Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma

Wu,

Li,

Long

et al. 2023

Sci Rep

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“… 22 Recently, a five-gene ( HDAC1, BIRC5, SPP1, STC2, and NR6A1 ) prognostic model was established for the prediction of overall survival in patients with HCC. 23 However, the performance of the model was only of acceptable predictive ability, and there was no in vitro or in vivo validation. 23 Moreover, the expression profile and molecular biological functions of NR6A1 during the development and progression of HCC, and its prognostic significance remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“… 23 However, the performance of the model was only of acceptable predictive ability, and there was no in vitro or in vivo validation. 23 Moreover, the expression profile and molecular biological functions of NR6A1 during the development and progression of HCC, and its prognostic significance remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Bioinformatics and the Role of NR6A1 in the Progression of HCC

Lin¹,

Zhang²,

Zhuang³

et al. 2022

J Clin Transl Hepatol

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Background and Aims: Generally acceptable prognostic models for hepatocellular carcinoma (HCC) are not available. This study aimed to establish a prognostic model for HCC by identifying immune-related differentially expressed genes (IR-DEGs) and to investigate the potential role of NR6A1 in the progression of HCC. Methods: Bioinformatics analysis using The Cancer Genome Atlas and ImmPort databases was used to identify IR-DEGs. Lasso Cox regression and multivariate Cox regression analysis were used to establish a prognostic model of HCC. Kaplan-Meier analysis and the receiver operating characteristic (ROC) curves were used to evaluate the performance of the prognostic model, which was further verified in the International Cancer Genome Consortium (ICGC) database. Gene set enrichment analysis was used to explore the potential pathways of NR6A1. Cell counting kit 8, colony formation, wound healing, and Transwell migration assays using Huh7 cells, and tumor formation models in nude mice were conducted. Results: A prognostic model established based on ten identified IR-DEGs including HSPA4, FABP6, MAPT, NDRG1, APLN, IL17D, LHB, SPP1, GLP1R, and NR6A1, effectively predicted the prognosis of HCC patients, was confirmed by the ROC curves and verified in ICGC database. NR6A1 expression was significantly up-regulated in HCC patients, and NR6A1 was significantly associated with a low survival rate. Gene set enrichment analysis showed the enrichment of cell cycle, mTOR, WNT, and ERBB signaling pathways in patients with high NR6A1 expression. NR6A1 promoted cell proliferation, invasiveness, migration, and malignant tumor formation and growth in vitro and in vivo. Conclusions: An effective prognostic model for HCC, based on a novel signature of 10 immune-related genes, was established. NR6A1 was up-regulated in HCC and was associated with a poor prognosis of HCC. NR6A1 promoted cell proliferation, migration, and growth of HCC, most likely through the cell cycle, mTOR, WNT, and ERBB signaling pathways.

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“…The FBXO17 and PPARGC1A genes were identified as gene signatures for colon cancer and could be useful in predicting the survival outcome and establishing the appropriate treatment strategy [ 20 ]. The HDAC1, BIRC5, SPP1, STC2, and NR6A1 genes have been proposed as prognostic models of immune genes in hepatocellular carcinoma [ 21 ]. The nine glycolysis-related genes were identified as predictive signatures and may function as independent and important risk factors for ovarian cancer [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

General Features and Novel Gene Signatures That Identify Epstein-Barr Virus-Associated Epithelial Cancers

Heawchaiyaphum

Pientong

Yoshiyama

et al. 2021

Cancers

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Epstein-Barr virus (EBV) is associated with various types of human malignancies, including nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC). The present study aimed to identify gene signatures and common signaling pathways that can be used to predict the prognosis of EBV-associated epithelial cancers (EBVaCAs) by performing an integrated bioinformatics analysis of cell lines and tumor tissues. We identified 12 differentially expressed genes (DEGs) in the EBVaCA cell lines. Among them, only four DEGs, including BAMBI, SLC26A9, SGPP2, and TMC8, were significantly upregulated. However, SLC26A9 and TMC8, but not BAMBI and SGPP2, were significantly upregulated in EBV-positive tumor tissues compared to EBV-negative tumor tissues. Next, we identified IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs. The expression of key genes related to the two hallmarks was upregulated in both EBV-infected cell lines and EBV-positive tumor tissues. These results suggest that SLC26A9 and TMC8 might be gene signatures that can effectively predict the prognosis of EBVaCAs and provide new insights into the molecular mechanisms of EBV-driven epithelial cancers.

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Identification, Verification and Pathway Enrichment Analysis of Prognosis-Related Immune Genes in Patients With Hepatocellular Carcinoma

Cited by 4 publications

References 36 publications

Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma

Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma

Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Bioinformatics and the Role of NR6A1 in the Progression of HCC

General Features and Novel Gene Signatures That Identify Epstein-Barr Virus-Associated Epithelial Cancers

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