Proteogenomic, Epigenetic, and Clinical Implications of Recurrent Aberrant Splice Variants in Clear Cell Renal Cell Carcinoma

Chang, Andrew C.; Chakiryan, Nicholas H.; Du, Dongliang; Stewart, Paul A.; Zhang, Yonghong; Tian, Yijun; Soupir, Alex C.; Bowers, Kiah; Fang, Bin; Morganti, Ashley; Teer, Jamie K.; Kim, Young‐Chul; Spiess, Philippe E.; Chahoud, Jad; Noble, Jerald D.; Putney, Ryan M.; Berglund, Anders; Robinson, Timothy J.; Koomen, John M.; Wang, Liang; Manley, Brandon J.

doi:10.1016/j.eururo.2022.05.021

Cited by 14 publications

(14 citation statements)

References 30 publications

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“…A total of 56 candidate upregulated genes were identified and were listed in Additional file 2 : Table S2. However, some of these genes, such as RNASET2 , TF , and ZIC2 , were already known to have an oncogenic role in the tumorigenesis, progression, and metastasis of renal cancer [ 24 – 26 ]. Among these candidate upregulated genes, VSX1 was selected and further analysis focused on the oncogenic role of VSX1 in ccRCC.…”

Section: Resultsmentioning

confidence: 99%

High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10

Yang

et al. 2022

J Transl Med

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Background Clear cell renal cell carcinoma (ccRCC), the most common urological malignancy, has an unfavorable prognosis and an unknown mechanism of progression. Through survival analyses screening of The Cancer Genome Atlas (TCGA) dataset, we identified Visual system homeobox1 (VSX1) as a novel potential prognostic biomarker in ccRCC and subsequently investigated the oncogenic role of VSX1 in ccRCC. Methods The differential expression of VSX1 in human tumors and the clinical prognoses were analyzed in the TCGA dataset and Gene Expression Omnibus. Spearman’s correlation coefficient was determined for the correlation analysis of VSX1 expression and other genes of interest. The roles of VSX1 in cell proliferation, invasion, and migration of ccRCC cells were evaluated via the CCK-8 assay, colony formation assay, and Transwell assay, respectively. Further results were demonstrated by western blotting, immunohistochemistry, qRT-PCR, tumor sphere formation, flow cytometry, and the dual‑luciferase reporter assay. Results VSX1 mRNA upregulation was generally observed in multiple human malignancies from the TCGA database and was confirmed in ccRCC clinical specimens from our department. High VSX1 expression usually indicated that overall and disease-free survival were unfavorable for patients with ccRCC. In terms of mechanism, knockdown or overexpression of VSX1 affected ccRCC aggressiveness in vitro. The dual-luciferase reporter gene assay implied that VSX1 overexpression significantly increased the luciferase activity of TMEM44, FKBP10, and TRIB3, which indicated that VSX1 promoted ccRCC invasiveness via transcriptional regulation of these genes. The significantly enhanced growth in vitro that was induced by stable VSX1 overexpression was almost restored to normal by the knockdown of FKBP10. Conclusions This study demonstrated that VSX1 was a novel prognostic biomarker in ccRCC and that high VSX1 expression promoted cell proliferation, invasion, and migration in ccRCC via transcriptional activation of downstream target genes.

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Section: Resultsmentioning

confidence: 99%

High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10

Yang

et al. 2022

J Transl Med

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“…It is thus interesting to note recent studies suggesting RNASET2 post-transcriptional gene regulation demonstrating mRNA-destabilizing allele-specific RNA-protein binding associated with RNASET2 GWAS risk variants ( 64 ). Likewise aberrant RNASET mRNA splice variants were associated with a poor prognosis in renal carcinoma ( 65 ). Using the POSTAR3 database a number of predicted T cell post-transcriptional mRNA-destabilizing RNA-protein binding motifs have been identified for RNASET mRNA as well as N6-Methyladenosine and Nm (2’-O-methylation) mRNA modification believed to be a key mechanism affecting mRNA translation and stability.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion

et al. 2022

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Ribonuclease T2 gene (RNASET2) variants are associated in genome wide association studies (GWAS) with risk for several autoimmune diseases, including Crohn’s disease (CD). In T cells, a functional and biological relationship exists between TNFSF15-mediated enhancement of IFN−γ production, mucosal inflammation and RNASET2. Disease risk variants are associated with decreased mRNA expression and clinical characteristics of severe CD; however, functional classifications of variants and underlying molecular mechanisms contributing to pathogenesis remain largely unknown. In this study we demonstrate that allelic imbalance of RNASET2 disease risk variant rs2149092 is associated with transcriptional and post-transcriptional mechanisms regulating transcription factor binding, promoter-transactivation and allele-specific expression. RNASET2 mRNA expression decreases in response to multiple modes of T cell activation and recovers following elimination of activator. In CD patients with severe disease necessitating surgical intervention, preoperative circulating RNASET2 protein levels were decreased compared to non-IBD subjects and rebounded post-operatively following removal of the inflamed region, with levels associated with allelic carriage. Furthermore, overexpression or treatment with recombinant RNASET2 significantly reduced IFN-γ secretion. These findings reveal that RNASET2 cis- and trans-acting variation contributed regulatory complexity and determined expression and provide a basis for linking genetic variation with CD pathobiology. These data may ultimately identify RNASET2 as an effective therapeutic target in a subset of CD patients with severe disease.

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“…Clear cell RCC (ccRCC) is the most common subtype of RCC, accounting for 85% of patients with RCC 2 . Surgery is the preferred treatment for early‐stage patients, but about 30% of postoperative patients still face recurrence 3 . Targeted therapy and immunotherapy are optional strategies for patients with advanced or nonoperative ccRCC 4 .…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin/FOXO3 enhances sunitinib resistance in clear cell renal cell carcinoma by inhibiting FDX1 expression and cuproptosis

Wang,

Jia,

Zhang

et al. 2023

The FASEB Journal

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Cuproptosis, a new type of copper‐induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib‐resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM‐regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance.

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Proteogenomic, Epigenetic, and Clinical Implications of Recurrent Aberrant Splice Variants in Clear Cell Renal Cell Carcinoma

Cited by 14 publications

References 30 publications

High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10

High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10

Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion

Adrenomedullin/FOXO3 enhances sunitinib resistance in clear cell renal cell carcinoma by inhibiting FDX1 expression and cuproptosis

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