Genes directly regulated by NF-κB in human hepatocellular carcinoma HepG2

Dai, Wei; Wu, Jian; Zhang, Shuyan; Shi, Bingjie; Xu, Xinhui; Wang, Danyang; Wang, Jinke

doi:10.1016/j.biocel.2017.05.031

Cited by 13 publications

(6 citation statements)

References 87 publications

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“…He finally successfully controlled flood and became the new king. Inspired by the Yu's strategy of controlling flood and based on our persistent studies of NF-κB [33][34][35][36][37][38][39][40][41][42][43], we thought that the constitutive activity of NF-κB in inflammatory and cancer cells may be utilize to treat these diseases. This strategy is contrary to the traditional inhibition of NF-κB.…”

Section: Introductionmentioning

confidence: 99%

Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting to telomere

Dai

Wang

et al. 2019

Preprint

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NF-κB has been a luring target for cancer therapy due to its over activation in all tumors. In this study, we showed that a gene therapy named as NF-κB-activated gene expression (Nage) could be used to induce cancer cell death in vitro and in vivo by utilizing the NF-κB activity in cancer cells; however, it had no effect on normal cells. In this gene therapy, we constructed a NF-κB-specific promoter by fusing a NF-κB decoy sequence to a minimal promoter, which could be bound by the intracellular over activated NF-κB and thus activate the expression of downstream effector gene in a NF-κB-specific manner. In this study, we firstly demonstrated the cancer cell-specific activation of NF-κB. We then demonstrated the cancer cell specificity of Nage vector expression by introducing a Nage vector that could express a reporter gene ZsGreen in various cell lines. We next demonstrated that a Nage vector that could express CRISPR/Cas9 protein and a telomeretargeting sgRNA could be used to specifically induce death of cancer cells. We finally showed that the Cas9/sgRNA Nage vector packaged into the adeno-associated virus (AAV) could be used to inhibit the growth of xenografted tumors in mouse by intravenously injecting recombinant AAV.

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Section: Introductionmentioning

confidence: 99%

Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting to telomere

Dai

Wang

et al. 2019

Preprint

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“…However, it controls other cellular functions, such as cell proliferation and differentiation. The target genes of NF‐κB include nearly all gene sets that govern the immune response, including genes encoding cytokines, chemokines, growth factors, transcription factors, apoptosis regulators and enzymes 11,12. In psoriasis, the constitutive activation of p65 in the epidermis has been discovered, and this sustained activation triggers the secretion of IL‐8 and CCL20 and aggravates the inflammatory response 13,14,15,16.…”

mentioning

confidence: 99%

Upregulated E3 ligase tripartite motif‐containing protein 21 in psoriatic epidermis ubiquitylates nuclear factor‐κB p65 subunit and promotes inflammation in keratinocytes*

Yang

Zhang

et al. 2020

Br J Dermatol

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Summary Background Tripartite motif‐containing protein 21 (Trim21) is an E3 ubiquitin‐protein ligase that plays pivotal roles in various diseases. However, its role in mediating keratinocyte inflammation, which is a hallmark of psoriasis, has not been thoroughly elucidated. Objectives To clarify whether Trim21 plays a pivotal role in regulating keratinocyte inflammation in psoriasis, while focusing on identifying key Trim21 substrates involved in mediating proinflammatory cytokine and chemokine production. Materials and methods Cytokine and chemokine secretion was examined by quantitative real‐time polymerase chain reaction (qPCR) in Trim21‐knockdown human keratinocytes. Downstream pathways and substrates of Trim21 were evaluated using immunoblotting, immunoprecipitation and immunofluorescence. The influence of Trim21 ubiquitination on its substrates was tested by in vitro ubiquitination assay, immunoprecipitation and immunofluorescence. The effectiveness of targeting Trim21 for psoriasis treatment was assessed in vivo with haematoxylin and eosin staining, immunofluorescence and qPCR. Results Knocking down Trim21 expression alleviated keratinocyte inflammation. Trim21 colocalized with p65/nuclear factor (NF)‐κB in the cytosol and physically bound and ubiquitinated p65 via a lysine 63 (K63) linkage. Instead of changing p65 protein stability, Trim21 enhanced the interaction of p65 with IκB kinase, which promoted p65 phosphorylation, nuclear transport and downstream gene activation. Finally, both in vitro and in vivo experiments verified that topical application of Trim21‐specific small interfering RNA markedly ameliorated imiquimod‐induced psoriasis‐like lesions. Conclusions Our study confirms that upregulated Trim21 in psoriatic epidermis ubiquitylates p65 and activates the NF‐κB pathway, which promotes keratinocyte inflammation. Hence, Trim21 represents a potential target for psoriasis treatment.

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“…The results showed that 64 immune-related genes were involved in the development and progression of HCC through immune pathways such as NF–kappa B signaling pathway, TNF signaling pathway, and Cytokine-cytokine receptor interaction. The over-activation of NF-kappa B has been found to be closely related to the pathogenesis of HCC ( Dai et al, 2017 ). PIGU (phosphatidylinositol glycan anchor biosynthesis class U) can decelerate the malignant progression of HCC by activating the NF-kappa B signaling pathway and promoting immune escape ( Wei et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Systematic Characterization of Novel Immune Gene Signatures Predicts Prognostic Factors in Hepatocellular Carcinoma

Wang

et al. 2021

Front. Cell Dev. Biol.

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Background: The prognosis of patients with hepatocellular carcinoma (HCC) is negatively affected by the lack of effective prognostic indicators. The change of tumor immune microenvironment promotes the development of HCC. This study explored new markers and predicted the prognosis of HCC patients by systematically analyzing immune characteristic genes.Methods: Immune-related genes were obtained, and the differentially expressed immune genes (DEIGs) between tumor and para-cancer samples were identified and analyzed using gene expression profiles from TCGA, HCCDB, and GEO databases. An immune prognosis model was also constructed to evaluate the predictive performance in different cohorts. The high and low groups were divided based on the risk score of the model, and different algorithms were used to evaluate the tumor immune infiltration cell (TIIC). The expression and prognosis of core genes in pan-cancer cohorts were analyzed, and gene enrichment analysis was performed using clusterProfiler. Finally, the expression of the hub genes of the model was validated by clinical samples.Results: Based on the analysis of 730 immune-related genes, we identified 64 common DEIGs. These genes were enriched in the tumor immunologic related signaling pathways. The first 15 genes were selected using RankAggreg analysis, and all the genes showed a consistent expression trend across multi-cohorts. Based on lasso cox regression analysis, a 5-gene signature risk model (ATG10, IL18RAP, PRKCD, SLC11A1, and SPP1) was constructed. The signature has strong robustness and can stabilize different cohorts (TCGA-LIHC, HCCDB18, and GSE14520). Compared with other existing models, our model has better performance. CIBERSORT was used to assess the landscape maps of 22 types of immune cells in TCGA, GSE14520, and HCCDB18 cohorts, and found a consistent trend in the distribution of TIIC. In the high-risk score group, scores of Macrophages M1, Mast cell resting, and T cells CD8 were significantly lower than those of the low-risk score group. Different immune expression characteristics, lead to the different prognosis. Western blot demonstrated that ATG10, PRKCD, and SPP1 were highly expressed in cancer tissues, while IL18RAP and SLC11A1 expression in cancer tissues was lower. In addition, IL18RAP has a highly positive correlation with B cell, macrophage, Neutrophil, Dendritic cell, CD8 cell, and CD4 cell. The SPP1, PRKCD, and SLC11A1 genes have the strongest correlation with macrophages. The expression of ATG10, IL18RAP, PRKCD, SLC11A1, and SPP1 genes varies among different immune subtypes and between different T stages.Conclusion: The 5-immu-gene signature constructed in this study could be utilized as a new prognostic marker for patients with HCC.

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Genes directly regulated by NF-κB in human hepatocellular carcinoma HepG2

Cited by 13 publications

References 87 publications

Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting to telomere

Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting to telomere

Upregulated E3 ligase tripartite motif‐containing protein 21 in psoriatic epidermis ubiquitylates nuclear factor‐κB p65 subunit and promotes inflammation in keratinocytes*

Systematic Characterization of Novel Immune Gene Signatures Predicts Prognostic Factors in Hepatocellular Carcinoma

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