TP53 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 the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.

Chimeric antigen receptor (CAR)-engineered T cells represent a promising modality for treating glioblastoma. Recently, we demonstrated that CAR-T cells targeting carbonic anhydrase IX (CAIX), a protein involved in HIF-1a hypoxic signaling, is a promising CAR-T cell target in an intracranial murine glioblastoma model. Anti-CAIX CAR-T cell therapy is limited by its suboptimal activation within the tumor microenvironment. LB-100, a small molecular inhibitor of protein phosphatase 2A (PP2A), has been shown to enhance T cell anti-tumor activity through activation of the mTOR signaling pathway. Herein, we investigated if a treatment strategy consisting of a combination of LB-100 and anti-CAIX CAR-T cell therapy produced a synergistic anti-tumor effect. Our studies demonstrate that LB-100 enhanced anti-CAIX CAR-T cell treatment efficacy in vitro and in vivo. Our findings demonstrate the role of LB-100 in augmenting the cytotoxic activity of anti-CAIX CAR-T cells and underscore the synergistic therapeutic potential of applying combination LB-100 and CAR-T Cell therapy to other solid tumors.

Aims: To identify the clinical roles of CLDN10 in clear cell renal cell carcinoma (ccRCC). Materials & methods: Using data from TCGA-KIRC, GEO DataSets and laboratory experiments to determine the p...

Diet and genetic risk are established risk factors for kidney cancer, but their interaction remains unclear. This study aims to systematically investigate the associations between various dietary patterns and kidney cancer risk, as well as to evaluate the combined effects of diet and genetic risk on kidney cancer risk. We conducted a prospective cohort study involving 113,594 participants from the UK Biobank who completed at least two 24-hour dietary recalls, and adherence to four dietary patterns (Alternate Mediterranean Index (aMED), Alternative Healthy Eating Index 2010 (AHEI), dietary approaches to stop hypertension (DASH), and dietary inflammatory index (DII)) was assessed. Incident kidney cancer cases were ascertained via records. Genetic risk was quantified using polygenic risk score (PRS). Associations were evaluated using Cox proportional hazards models, adjusting for confounders. Furthermore, mediation analyses were conducted to identify potential mediators. During a median follow-up of 11.44 years, 425 participants developed kidney cancer. Higher aMED (HR = 0.71, 95% CI: 0.54–0.94) and DASH (HR = 0.67, 95% CI: 0.49–0.90) were associated with reduced risk of kidney cancer, while higher DII was associated with increased risk (HR = 1.36, 95% CI: 1.02–1.79). Moreover, participants with high genetic risk combined with low aMED, AHEI and DASH scores or high DII score presented the highest kidney cancer risk. Additive interaction was observed between genetic risk and AHEI as well as DII. Moreover, a series of biochemical indicators were identified as potential mediators, with the mediation proportions ranging from 0.76% to 8.40%. Adherence to healthy dietary patterns, such as aMED, AHEI, and DASH is associated with a reduced risk of kidney cancer, whereas a pro-inflammatory diet confers a greater risk, particularly in high-genetic-risk populations. These findings provide strong evidence that promoting these healthy dietary patterns represents a promising public health strategy for the primary prevention of kidney cancer. Adherence to healthy dietary patterns (aMED, AHEI, and DASH) is associated with a lower risk of kidney cancer. A pro-inflammatory diet, measured by the Dietary Inflammatory Index (DII), is linked to a higher kidney cancer risk. Genetic susceptibility amplifies the associations between dietary patterns and kidney cancer incidence. Dietary modification may be a particularly impactful public health strategy for kidney cancer prevention, especially in genetically high-risk populations.

Recent evidences have suggested that Zinc finger protein 582 (ZNF582) plays different important roles in various tumors, but its clinical role, biological function and regulatory mechanism in clear cell renal cell carcinoma (ccRCC) are still vague. Through analyzing GEO and TCGA-KIRC data and validation with local samples, we identified the low expression pattern of ZNF582 in ccRCC. Decreased ZNF582 expression is correlated with higher tumor stage and grade, distant metastasis and poor prognosis. By analyzing the DNA methylation data of ccRCC in TCGA-KIRC and using Massarray DNA methylation and demethylation analysis, we confirmed the hypermethylation status of ZNF582 in ccRCC and its negative regulation on ZNF582 expression. Using cell phenotype experiments and orthotopic kidney tumor growth models, we determined the inhibitory effect of ZNF582 overexpression on ccRCC growth and metastasis in vivo and in vitro. Mechanistically, using TMT (Tandem mass tags) quantitative proteomics test, Co-IP (Co-immunoprecipitation) and Western Blot experiments, we clarified that ZNF582 binds to TJP2 and up-regulates TJP2 protein expression. Increased TJP2 protein combines with ERK2 to promote ERK2 protein expression and suppresses the phosphorylation of ERK2, thereby inhibiting the growth and metastasis of ccRCC. In general, our findings provide the first solid theoretical rationale for targeting ZNF582/TJP2/ERK2 axis to improve ccRCC treatment.