RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway

Liu, Jian Ye; Zeng, Qing; Cao, Peiguo; Xie, Dan; Chen, Xin; Yang, Fei; He, Lan; Dai, Ying; Li, Jing Jing; Liu, Xiao Ming; Zeng, Hong; Zhu, Yi; Gong, Lian; Cheng, Yan; Zhou, Jiayi; Hu, Jun; Bo, Hao; Xu, Zhen; Cao, Ke

doi:10.1038/s41416-018-0116-8

Cited by 48 publications

(46 citation statements)

References 44 publications

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“…RIPK4 inactivation inhibited NF-κB activity, impaired the survival of DLBCL cells, and sensitized DLBCL cells to the treatment with chemotherapeutic agents (57). Consistent with previous studies in bladder urothelial carcinoma, the oncogenic activity of RIPK4 depended on the activation of NF-κB, leading to increased vascular endothelial growth factor A (VEGF-A) levels, which ultimately mediated the RIPK4induced EMT and promoted bladder urothelial carcinoma cell aggressiveness (58). RIPK4 overexpression promoted the growth of nasopharyngeal carcinoma (NPC) cells.…”

Section: The Role Of Ripk4 In Carcinogenesissupporting

confidence: 86%

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Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

Wei

2020

Front. Oncol.

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The receptor-interacting protein kinase 4 (RIPK4), a member of the RIPK family, was originally described as an interaction partner of protein kinase C (PKC) β and PKCδ. RIPK4 is identified as a key regulator of keratinocyte differentiation, cutaneous inflammation, and cutaneous wound repair. The mechanism by which RIPK4 integrates upstream signals to initiate specific responses remains elusive. Previous studies have indicated that RIPK4 can regulate several signaling pathways, including the NF-κB, Wnt/β-catenin, and RAF/MEK/ERK pathways. Furthermore, RIPK4-related biological signaling pathways interact with each other to form a complex network. Mounting evidence suggests that RIPK4 is aberrantly expressed in various kinds of cancers. In several types of squamous cell carcinoma (SCC), the mutations that drive aggressive SCC have been found in RIPK4. In addition, the function of RIPK4 in carcinogenesis is probably tissue-specific, since RIPK4 can play a dual role as both a tumor promoter and a tumor suppressor in different tumor types. Therefore, RIPK4 may represent as an independent prognostic factor and a promising novel therapeutic target, which can be used to identify the risks of patients and guide personalized treatments. In future, RIPK4-interacting pathways and precise molecular targets need to be investigated in order to further elucidate the mechanisms underlying epidermal differentiation and carcinogenesis.

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Section: The Role Of Ripk4 In Carcinogenesissupporting

confidence: 86%

“…On the contrary, mounting evidence has demonstrated the oncogenic role of RIPK4 (20,21,46,(57)(58)(59). RIPK4 knockdown in A2780 and COV434 ovarian cancer cells could inhibit βcatenin accumulation and RIPK4 overexpression could promote ovarian cancer in a xenograft tumor model (20).…”

Section: The Role Of Ripk4 In Carcinogenesismentioning

confidence: 99%

Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

Wei

2020

Front. Oncol.

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“…Seven of the eight hub genes are reported to directly participate in the identified pathways, except for RIPK4. Additionally, our previous study found that upregulation of RIPK4 increases the expression of VEGFA and contributes to the progression of bladder urothelial carcinoma [56].…”

Section: Ppimentioning

confidence: 92%

A network-based approach to identify DNA methylation and its involved molecular pathways in testicular germ cell tumors

Cao

Tang

et al. 2019

J. Cancer

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Background : Testicular germ cell tumors (TGCT) is the most common testicular malignancy threaten young male reproductive health. This study aimed to identify aberrantly methylated-differentially expressed genes and pathways in TGCT by comprehensive bioinformatics analysis. Methods : Data of gene expression microarrays (GSE3218, GSE18155) and gene methylation microarrays (GSE72444) were collected from GEO database. Integrated analysis acquired aberrantly methylated-genes. Functional and pathway enrichment analysis were performed using DAVID database. Protein-protein interaction (PPI) network was constructed by STRING and App Mcode was used for module analysis. GEPIA platform and DiseaseMeth database were used for confirming the expression and methylation levels of hub genes. Finally, Human Protein Atlas database was performed to evaluate the prognostic significance. Results : Totally 604 hypomethylation-high expression and 147 hypermethylation-low genes were identified. The high expressed genes were enriched in biological processes of cell proliferation and migration. The top 8 hub genes of PPI network were GAPDH, VEGFA, PTPRC, RIPK4, MMP9, CSF1R, KRAS and FN1. After validation in GEPIA platform, all hub genes were elevated in TGCT tissues. Only MMP9, CSF1R and PTPRC showed hypomethylation-high expression status, which predicted the poor outcome of TGCT patients. Conclusion : Our study indicated possible aberrantly methylated-differentially expressed genes and pathways in TGCT by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of TGCT.

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“…Furthermore, PPI network analysis identified that RIPK4, TNF, CDC42, KNG1, PTPN11, KITLG, PTGS2, SYK, IGF1R, EPO, SERPINE1, FLT1, AURKB, GNA13, DLG2, ACTN2, CHEK1, FGF8, CD80 and MCHR2 had the highest degree of connectivity among DEGs. RIPK4 could promote cancer cell aggressiveness by upregulate VEGF-A [30]. TNF mediates resistance to EGFR inhibition in cancer [31,32].…”

Section: Discussionmentioning

confidence: 99%

The Identification of Key Gene Expression Signature and Biological Pathways in Metastatic Renal Cell Carcinoma

et al. 2020

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Purpose: To investigate the potential mechanisms contributing to metastasis of clear cell renal cell carcinoma (ccRCC), screen the hub genes, associated pathways of metastatic ccRCC and identify potential biomarkers. Methods: The ccRCC metastasis gene expression profile GSE47352 was employed to analyze the differentially expressed genes (DEGs). DAVID was performed to assess Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The protein-protein interaction (PPI) network and modules were constructed. The function pathway, prognostic and diagnostic analysis of these hub genes was picked out to estimate their potential effects on metastasis of ccRCC. Results: A total of 873 DEGs were identified (503 upregulated genes and 370 downregulated genes). Meanwhile, top 20 hub genes were displayed. GO analysis showed that the top 20 hub genes were enriched in regulation of phosphatidylinositol 3-kinase signaling, positive regulation of DNA replication, protein autophosphorylation, protein tyrosine kinase activity, etc. KEGG analysis indicated these hub genes were enriched in the Ras signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, Pathways in cancer, etc. The GO and KEGG enrichment analyses for the hub genes disclosed important biological features of metastatic ccRCC. PPI network showed the interaction of top 20 hub genes. Gene Set Enrichment Analysis (GSEA) revealed that some of the hub genes was associated with metastasis, epithelial mesenchymal transition (EMT), hypoxia cancer and adipogenesis of ccRCC. Some top hub genes were distinctive and new discoveries compared with that of the existing associated researches. Conclusions: Our analysis uncovered that changes in signal pathways such as Ras signaling pathway, PI3K-Akt signaling pathway, etc. may be the main signatures of metastatic ccRCC. We identified several candidate biomarkers related with overall survival (OS) and disease-free survival (DFS) of ccRCC patients. Accordingly, they might be novel therapeutic targets and used as potential biomarkers for diagnosis, prognosis of ccRCC.

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RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway

Abstract: Our data highlighted the molecular aetiology and clinical significance of RIPK4 in BC: upregulation of RIPK4 contributes to NF-κB activation, and upregulates VEGF-A, and BC progression. Targeting RIPK4 might represent a new therapeutic strategy to improve survival for patients with BC.

Cited by 48 publications

References 44 publications

Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

A network-based approach to identify DNA methylation and its involved molecular pathways in testicular germ cell tumors

The Identification of Key Gene Expression Signature and Biological Pathways in Metastatic Renal Cell Carcinoma

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