Cell cycle arrest and senescence in P53-wild type renal carcinoma by enhancer RNA - P53-bound enhancer regions 2(p53BER2) through p53-dependent pathway

Abstract Background P53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through p53 enhancer RNA-related pathway. Methods qPCR and luciferase reporters were used to detect the expression of p53-related enhancer RNA. Nutlin3 and artificial "microRNA" were used to induce and inhibit the expression of p53 enhancer RNA, respectively. Cycle analysis and β-galactosidase assay were used to explore whether P53-bound enhancer regions 2(p53BER2) plays a role in the cell cycle and senescence response of p53-wild type (WT) renal cancer cells. The function of p53BER2 was further analyzed in vivo by nude mice. RNA sequencing was used to identify the potential target of p53BER2. Results The results showed that P53BER2 expression was down-regulated in renal cancer tissues and cell lines and could specifically express in p53-WT renal cancer cell lines. Knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in p53-WT cell lines. Further, downregulation of p53BER2 could reverse nutlin-3-induced G1 arrest and senescence in p53-WT cell lines. What is more, knockdown of p53BER2 showed a resistance to nutlin-3 treatment in Vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo, which suggested BRCA2 might mediate the function of p53BER2 in RCC. Conclusions The p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in p53-WT renal cancer cells. This further provides a novel approach and insight for the RCC and p53 research in renal cancer.

Discovery and validation of the prognostic value of the lncRNAs encoding snoRNAs in patients with clear cell renal cell carcinoma

MP14-15 INTRA-FAMILIAL PHENOTYPIC HETEROGENEITY IN VON HIPPEL-LINDAU DISEASE: IMPLICATIONS FOR PERSONALIZED SURVEILLANCE PLAN

MP16-03 DOWNREGULATION AND FREQUENT PROMOTER HYPERMETHYLATION OF CLDN7 CORRELATE WITH TUMOR PROGRESSION AND POOR PROGNOSIS IN HUMAN CLEAR CELL RENAL CELL CARCINOMA

Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors

The Efficacy and Safety of Tyrosine Kinase Inhibitors for Von Hippel–Lindau Disease: A Retrospective Study of 32 Patients

Differential Expression of PD-L1 Between Sporadic and VHL-Associated Hereditary Clear-Cell Renal Cell Carcinoma and Its Correlation With Clinicopathological Features

Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel–Lindau Disease

Intra-familial phenotypic heterogeneity and telomere abnormality in von Hippel-Lindau disease

AbstractVon Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p=0.834) and between first-born patients and the other siblings (p=0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

Genotype and phenotype correlation in von Hippel–Lindau disease based on alteration of the HIF-α binding site in VHL protein

Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis

Clinicopathologic Features and Prognosis of Sporadic Bilateral Renal Cell Carcinoma: A Series of 148 Cases

PD04-07 HIGHER PD-L1 MRNA LEVEL IN CLEAR CELL RENAL CELL CARCINOMAS IS ASSOCIATED WITH A FAVORABLE OUTCOME

Peking University - Juntendo University Joint Symposium on Cancer Research and Treatment

Genotype-phenotype correlations in Chinese von Hippel–Lindau disease patients

MP71-15 VHL GENE MUTATION SPECTRUM AND GENOTYPE-PHENOTYPE CORRELATIONSHIP OF CHINESE VHL PATIENTS

Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential: A Series of 76 Cases

Higher programmed cell death 1 ligand 1 (PD-L1) mRNA level in clear cell renal cell carcinomas is associated with a favorable outcome due to the active immune responses in tumor tissues

Renal Arterial Pseudoaneurysm and Renal Arteriovenous Fistula Following Partial Nephrectomy

Association between FBP1 and hypoxia-related gene expression in clear cell renal cell carcinoma

Higher Prevalence of Novel Mutations in VHL Gene in Chinese Von Hippel-Lindau Disease Patients

Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients

The Erythropoietin/Erythropoietin Receptor Signaling Pathway Promotes Growth and Invasion Abilities in Human Renal Carcinoma Cells

Growth pattern of renal cell carcinoma (RCC) in patients with delayed surgical intervention

THE RELATIONSHIP OF EPO OVER-EXPRESSION TO VHL MUTATIONS AND Hif1α AND 2α IN SCCRCC

Multilocular cystic renal cell carcinoma: an experience of clinical management for 31 cases

Coexpression of erythropoietin and erythropoietin receptor in sporadic clear cell renal cell carcinoma

363: Somatic Mutations of the Von Hippel-Lindau (VHL) Tumor Suppressor Gene, Expression of Hypoxia Inducible Factor-α and Vascula Endothelial Growth Factor in Chinese Sporadic Clear Cell Renal Cell Carcinomas and Their Relationships to Angiogenesis