Genomics of Clear-cell Renal Cell Carcinoma: A Systematic Review and Meta-analysis

Bui, Oanh Thi; Dao, Van Tu; Nguyen, Tai Van; Feugeas, Jean-Paul; Pamoukdjian, Frédéric; Bousquet, Guilhem

doi:10.1016/j.eururo.2021.12.010

Cited by 74 publications

(49 citation statements)

References 52 publications

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“…Specific genetic mutations and epigenetically disrupted genes are good candidate targets for prognostic and diagnostic tools and treatment strategy [ 35 , 36 ]. The cBioPortal database was used to analyzed genetic alteration in NR1H4 and its associations with OS and PFS (progression free survival) of ccRCC patients.…”

Section: Resultsmentioning

confidence: 99%

Clinical significance and oncogenic function of NR1H4 in clear cell renal cell carcinoma

Huang

Hou

et al. 2022

BMC Cancer

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Background Nuclear receptor subfamily 1 group H member 4 (NR1H4) have been reported in various cancer types, however, little is known about the clinical values and biological function in clear cell Renal cell carcinoma (ccRCC). Methods The expression pattens of NR1H4 in ccRCC were investigated in clinical specimens, cell lines and publicly‑available databases. Cell Counting Kit-8 (CCK-8), colony formation, 5-ethynyl-2' -deoxyuridine (EdU), transwell and cell wound healing assays were performed to assess the biological functions of NR1H4 in 786-O ccRCC cells. Gene set enrichment analysis (GSEA), Flow Cytometry, quantitative real‐time PCR (qRT-PCR), western blot and immunofluorescence were performed to explore the molecular mechanism of NR1H4 in ccRCC. We explored the early diagnostic value, prognostic value, genetic mutation and DNA methylation of NR1H4 by a comprehensive bioinformatics analysis based on the data published in the following databases: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Kaplan‐Meier Plotter, Gene Expression Profiling Interactive Analysis (GEPIA), UNIVERSITY OF CALIFORNIA SANTA CRUZ Xena (UCSC Xena), cBio Cancer Genomics Portal, MethSurv, SurvivalMeth and The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN). Its correlation with tumor-infiltrating immune cells in ccRCC was analyzed by Tumor Immune Estimation Resource 2.0 (TIMER2.0) and Tumor Immune System Interactions Database (TISIDB). Results In this study, NR1H4 was found to be highly expressed in ccRCC tissues and ccRCC cell lines. Knockdown of NR1H4 significantly suppressed cancer cell proliferation, migration and invasion. Mechanistically, tumor‐associated signaling pathways were enriched in the NR1H4 overexpression group and si-NR1H4 could induce the downregulation of Cyclin E2 (CCNE2). By bioinformatics analysis, NR1H4 was identified as highly expressed in stage I ccRCC with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.8). Genetic alteration and DNA methylation of NR1H4 were significantly associated with prognosis in ccRCC patients. Moreover, NR1H4 expression associated with immune cell infiltration levels in ccRCC, which provides a new idea for immunotherapy. Conclusions Our study indicated that NR1H4 might be a potential tumor biomarker and therapeutic target for ccRCC which could promote cancer cell proliferation, migration and invasion via regulating CCNE2.

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Section: Resultsmentioning

confidence: 99%

Clinical significance and oncogenic function of NR1H4 in clear cell renal cell carcinoma

Huang

Hou

et al. 2022

BMC Cancer

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“…The trigger for the micronuclei formation in normal PTEC has been attributed to their susceptibility to hypoxic microenvironments, a hallmark in ccRCC progression (11,12). Alteration in VHL expression, present in 80%-93% of primary ccRCC cases, forms a selfperpetuating hypoxic PTEC microenvironment (13)(14)(15)(16)(17).…”

Section: Cellular Origin Of Ccrcc-all Paths Lead To Ccrccmentioning

confidence: 99%

Cellular milieu in clear cell renal cell carcinoma

et al. 2022

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Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC.

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“…For advanced renal cancer patients with distant tumor metastasis, only half of the patients survive for more than one year, and only 10% of patients survive for more than five years [ 4 , 5 ]. Although the survival rate for patients with metastatic RCC has increased significantly due to continuous research and development of antiangiogenic drug-targeted therapy and immunotherapy, long-term drug resistance generally leads to treatment failure [ 6 – 8 ]. Therefore, identifying and exploring new molecular markers that cause cancer and exploiting these as targets for gene therapy has become a high-priority topic in current cancer treatment research.…”

Section: Introductionmentioning

confidence: 99%

ARL4C Regulates the Progression of Clear Cell Renal Cell Carcinoma by Affecting the Wnt/β-Catenin Signaling Pathway

Zhang

Chen

et al. 2022

Journal of Oncology

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Purpose. To investigate the expression of the ADP-ribosylation factor (ARF)-like proteins (ARLs) and ARL4C in clear cell renal cell carcinoma (ccRCC) based on bioinformatics analysis and experimentally determine the effect and mechanism of ARL4C on cellular properties involved in ccRCC progression. Methods. After downloading the data of cancer patients from the TCGA database, we used various bioinformatics analysis websites and methods to analyze the expression and function of ARLs and ARL4C. The differential expression of ARL4C in clinical renal cancer tissues versus adjacent normal tissues was further verified using immunohistochemistry and real-time quantitative reverse-transcription (qRT-PCR). qRT-PCR was used to explore the expression of ARL4C mRNA in normal renal cells versus different ccRCC cell lines, and the protein expression of ARL4C was further verified using western blotting. CCK-8, colony formation, and EdU assays were used to determine the effect of ARL4C knockdown on ccRCC cell proliferation. We also used wound healing and Transwell assays to analyze the changes in ccRCC cell migration and invasion following ARL4C knockdown. Finally, we used western blotting to probe the molecular mode of action of ARL4C in ccRCC cells after exposure to Wnt signaling pathway agonists. Results. Biological function analysis showed that methylation of ARL4C and changes in immune cell infiltration and targeted drug sensitivity caused by altered ARL4C expression affected the prognosis of ccRCC. Further bioinformatics analysis suggested that the expression of ARL4C mRNA was increased in ccRCC, and this was associated with a poor prognosis in ccRCC patients. Increased expression of ARL4C was further verified using qRT-PCR and western blotting of human ccRCC tissue samples. Downregulation of ARL4C significantly inhibited the proliferation, migration, and invasion of ccRCC cells, and activation of the Wnt/β-catenin pathway promoted the expression of ARL4C. As an essential downstream effector of the Wnt signaling pathway, ARL4C increased the expression of cyclin D1 and c-myc, thereby increasing the ability of the cells to undergo epithelial-mesenchymal transition (EMT) and ccRCC progression. Conclusions. As a critical factor in the Wnt/β-catenin pathway, ARL4C regulates EMT and progression in ccRCC.

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Genomics of Clear-cell Renal Cell Carcinoma: A Systematic Review and Meta-analysis

Cited by 74 publications

References 52 publications

Clinical significance and oncogenic function of NR1H4 in clear cell renal cell carcinoma

Clinical significance and oncogenic function of NR1H4 in clear cell renal cell carcinoma

Cellular milieu in clear cell renal cell carcinoma

ARL4C Regulates the Progression of Clear Cell Renal Cell Carcinoma by Affecting the Wnt/β-Catenin Signaling Pathway

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