Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer.

Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What's more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.

Identification of mRNA vaccines and conserved ferroptosis related immune landscape for individual precision treatment in bladder cancer.

Background: The aim of this study was to identify the ferroptosis induced tumor microenvironment (FeME) landscape in bladder cancer (BCa) for mRNA vaccine development and selecting suitable patients for precision treatment. Methods: Gene expression profiles and clinical information of 1216 BCa patients were extracted from TCGA-BLCA, three GEO databases and IMvigor210 cohort. We comprehensively established the FeME landscape of 1216 BCa samples based on 290 ferroptosis related genes (FRGs), and systematically correlated these regulation patterns with TME cell-infiltrating characteristics. Besides, we identified the patients' ferroptosis risk index (FRI) to predict the prognosis of BCa for precise treatment. Results: Six over-expressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in BCa. Furthermore, we demonstrated the evaluation of FeME within individual tumors could predict stages of tumor inflammation, subtypes, genetic variation, and patient prognosis. Then, 5-lncRNA signature was mined to produce the FRI. Low FRI was also linked to increased mutation load, better prognosis and enhanced response to anti-PD-L1 immunotherapy. Besides, an immunotherapy cohort confirmed patients with lower FRI demonstrated significant therapeutic advantages and clinical benefits. Conclusions: TFRC, SCD, G6PD, FADS2, SQLE, and SLC3A2 are potent antigens for developing anti-BCa mRNA vaccine. Establishment of FRI will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies and selecting appropriate patients for tumor vaccine therapy. Supplementary Information: The online version contains supplementary material available at 10.1186/s40537-022-00641-z.

An Aging and Senescence-Related Gene Signature for Prognosis Prediction in Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common solid lesion in the kidney. This study aims to establish an aging and senescence-related mRNA model for risk assessment and prognosis prediction in ccRCC patients. Methods: ccRCC data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. By applying univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression, a new prognostic model based on aging and senescence-related genes (ASRGs) was established. Depending on the prognostic model, high- and low-risk groups were identified for further study. The reliability of the prediction was evaluated in the validation cohort. Pan-cancer analysis was conducted to explore the role of GNRH1 in tumors. Results: A novel prognostic model was established based on eight ASRGs. This model was an independent risk factor and significantly correlated with the prognosis and clinicopathological features of ccRCC patients. The high- and low-risk groups exhibited distinct modes in the principal component analysis and different patterns in immune infiltration. Moreover, the nomogram combining risk score and other clinical factors showed excellent predictive ability, with AUC values for predicting 1-, 3-, and 5-year overall survival in the TCGA cohort equal to 0.88, 0.82, and 0.81, respectively. Conclusion: The model and nomogram based on the eight ASRGs had a significant value for survival prediction and risk assessment for ccRCC patients, providing new insights into the roles of aging and senescence in ccRCC.

Identification of ZDHHC1 as a Pyroptosis Inducer and Potential Target in the Establishment of Pyroptosis-Related Signature in Localized Prostate Cancer.

Pyroptosis or cellular inflammatory necrosis is a programmed cell death kind. Accumulating evidence shows that pyroptosis plays a crucial role in the invasion, metastasis, and proliferation of tumor cells, thus affecting the prognosis of tumors and therapeutic effects. Prostate cancer (PCa), a common malignancy among men, is associated with inflammation. Pathophysiological effects of pyroptosis on tumor development and progression, as well as the mediation of PCa, are known, but its effects on the potential prognosis for PCa warrant in-depth investigation. Herein, we built a risk model of six pyroptosis-related genes and verified their predictive abilities for prognostic and therapeutic effects. Higher risk scores indicated a higher probability of biochemical recurrence (BCR), higher immune infiltration, and worsened clinicopathological features. To derive scientific and reliable predictions for BCR in patients having PCa, the findings of the current study were verified in the Gene Expression Omnibus (GEO) cohort following evaluation in The Cancer Genome Atlas (TCGA) dataset. Additionally, after evaluating the six genes in the model, ZDHHC1 was found to be an important component. Its antitumor role was further assessed through in vivo and in vitro experiments, and its promoting effect on pyroptosis was further evaluated and verified. The above results provided a new perspective for further studies on pyroptosis and its clinical utility for PCa.

circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis.

BACKGROUND: Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC. METHODS: circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization. RESULTS: The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression. CONCLUSIONS: We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.

AGAP2-AS1/miR-628-5p/FOXP2 feedback loop facilitates the growth of prostate cancer via activating WNT pathway.

Increasing studies have indicated the critical roles of long non-coding RNAs (lncRNAs) in the tumorigenesis of cancers. LncRNA AGAP2 antisense RNA 1 (AGAP2-AS1) can serve as an oncogenic role in some cancers, including prostate cancer (PCa). However, the underling mechanism of such lncRNA in PCa has not been fully studied. Therefore, it is meaningful to investigate the role and underlying mechanism of AGAP2-AS1 in PCa. AGAP2-AS1 was confirmed to be highly expressed in PCa cells. Functionally, AGAP2-AS1 silencing inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition process and induced apoptosis. According to mechanism assays, AGAP2-AS1 sponged miR-628-5p, which was found to restrain PCa cell growth. Besides, FOXP2 was identified as a target gene of miR-628-5p, and its expression was negatively regulated by miR-628-5p and positively modulated by AGAP2-AS1. Importantly, we found that FOXP2 could function as the upstream gene of AGAP2-AS1. Through rescue experiments, we discovered that FOXP2 up-regulation countered AGAP2-AS1 knockdown-mediated inhibition on PCa cell growth. Finally, it was found that AGAP2-AS1 could activate WNT pathway, and LiCl could reverse the influence of AGAP2-AS1 on PCa biological behaviors. To conclude, AGAP2-AS1/miR-628-5p/FOXP2 feedback loop facilitated PCa cell growth via activating WNT pathway.

Preoperative CT Radiomics Predicting the SSIGN Risk Groups in Patients With Clear Cell Renal Cell Carcinoma: Development and Multicenter Validation.

Objective: The stage, size, grade, and necrosis (SSIGN) score can facilitate the assessment of tumor aggressiveness and the personal management for patients with clear cell renal cell carcinoma (ccRCC). However, this score is only available after the postoperative pathological evaluation. The aim of this study was to develop and validate a CT radiomic signature for the preoperative prediction of SSIGN risk groups in patients with ccRCC in multicenters. Methods: In total, 330 patients with ccRCC from three centers were classified into the training, external validation 1, and external validation 2 cohorts. Through consistent analysis and the least absolute shrinkage and selection operator, a radiomic signature was developed to predict the SSIGN low-risk group (scores 0-3) and intermediate- to high-risk group (score ≥ 4). An image feature model was developed according to the independent image features, and a fusion model was constructed integrating the radiomic signature and the independent image features. Furthermore, the predictive performance of the above models for the SSIGN risk groups was evaluated with regard to their discrimination, calibration, and clinical usefulness. Results: A radiomic signature consisting of sixteen relevant features from the nephrographic phase CT images achieved a good calibration (all Hosmer-Lemeshow p > 0.05) and favorable prediction efficacy in the training cohort [area under the curve (AUC): 0.940, 95% confidence interval (CI): 0.884-0.973] and in the external validation cohorts (AUC: 0.876, 95% CI: 0.811-0.942; AUC: 0.928, 95% CI: 0.844-0.975, respectively). The radiomic signature performed better than the image feature model constructed by intra-tumoral vessels (all p < 0.05) and showed similar performance with the fusion model integrating radiomic signature and intra-tumoral vessels (all p > 0.05) in terms of the discrimination in all cohorts. Moreover, the decision curve analysis verified the clinical utility of the radiomic signature in both external cohorts. Conclusion: Radiomic signature could be used as a promising non-invasive tool to predict SSIGN risk groups and to facilitate preoperative clinical decision-making for patients with ccRCC.

A Computed Tomography-Based Radiomics Nomogram to Preoperatively Predict Tumor Necrosis in Patients With Clear Cell Renal Cell Carcinoma.

Objective: To develop and validate a radiomics nomogram for preoperative prediction of tumor necrosis in patients with clear cell renal cell carcinoma (ccRCC). Methods: In total, 132 patients with pathologically confirmed ccRCC in one hospital were enrolled as a training cohort, while 123 ccRCC patients from second hospital served as the independent validation cohort. Radiomic features were extracted from corticomedullary and nephrographic phase contrast-enhanced computed tomography (CT) images. A radiomics signature based on optimal features selected by consistency analysis and the least absolute shrinkage and selection operator was developed. An image features model was constructed based on independent image features according to visual assessment. By integrating the radiomics signature and independent image features, a radiomics nomograph was constructed. The predictive performance of the above models was evaluated using receiver operating characteristic (ROC) curve analysis. Furthermore, the nomogram was assessed using calibration curve and decision curve analysis. Results: Thirty-seven features were used to establish a radiomics signature, which demonstrated better predictive performance than did the image features model constructed using tumor size and intratumoral vessels in the training and validation cohorts (p <0.05). The radiomics nomogram demonstrated satisfactory discrimination in the training (area under the ROC curve [AUC] 0.93 [95% CI 0.87-0.96]) and validation (AUC 0.87 [95% CI 0.79-0.93]) cohorts and good calibration (Hosmer-Lemeshow p>0.05). Decision curve analysis verified that the radiomics nomogram had the best clinical utility compared with the other models. Conclusion: The radiomics nomogram developed in the present study is a promising tool to predict tumor necrosis and facilitate preoperative clinical decision-making for patients with ccRCC.