To evaluate the validity of CHAC1 for predicting the prognosis of kidney renal clear cell carcinoma (KIRC) and to explore its therapeutic potential for KIRC, we conducted several bioinformatic analyses using the sequencing data and clinical information derived from online databases. We found CHAC1 is down‐regulated in KIRC samples when compared with normal samples but up‐regulated in KIRC samples with relatively higher malignancy and later stages. Univariate cox analysis and multivariate cox regression analysis were conducted and the results revealed up‐regulated CHAC1 is an independent risk factor for poor prognosis of KIRC. Further, the nomogram model based on the result of multivariate cox regression analysis was constructed and effectively predicted patients' 1‐year, 3‐year and 5‐year survival respectively. The correlation analyses showed CHAC1 is associated with the immune pathway markers of memory B cell, natural killer cell and type1 T helper cell as well as the checkpoint genes like ADORA2A, CD200, CD44, CD70, HHLA2, NRP1, PDCD1LG2 and TNFRSF18. Furthermore, experiments in vitro indicated CHAC1 could induce cell death in KIRC cell lines but had limited influence on cell migration and cell invasion. In conclusion, CHAC1 is found a valid indicator for poor prognosis of kidney renal clear cell carcinoma.

To establish and internally validate an innovative R.I.R.S. scoring system that allows urologists to preoperatively estimate the stone-free rate (SFR) after retrograde intrarenal surgery (RIRS). This study included 382 eligible samples from a total 573 patients who underwent RIRS from January 2014 to December 2016. Four reproducible factors in the R.I.R.S. scoring system, including renal stone density, inferior pole stone, renal infundibular length and stone burden, were measured based on preoperative computed tomography of urography to evaluate the possibility of stone clearance after RIRS. The median cumulative diameter of the stones was 14 mm, and the interquartile range was 10 to 21. The SFR on postoperative day 1 in the present cohort was 61.5% (235 of 382), and the final SFR after 1 month was 73.6% (281 of 382). We established an innovative scoring system to evaluate SFR after RIRS using four preoperative characteristics. The range of the R.I.R.S. scoring system was 4 to 10. The overall score showed a great significance of stone-free status (p < 0.001). The area under the receiver operating characteristic curve of the R.I.R.S. scoring system was 0.904. The R.I.R.S. scoring system is associated with SFR after RIRS. This innovative scoring system can preoperatively assess treatment success after intrarenal surgery and can be used for preoperative surgical arrangement and comparisons of outcomes among different centers and within a center over time.

Relaxin abrogates renal interstitial fibrosis by regulating macrophage polarization via inhibition of Toll-like receptor 4 signaling

As the most common modification of RNA, N⁶-methyladenosin (m⁶A) has been confirmed to be involved in the occurrence and development of various cancers. However, the relationship between m⁶A and castration resistance prostate cancer (CRPC), has not been fully studied. By m⁶A-sequencing of patient cancer tissues, we identified that the overall level of m⁶A in CRPC was up-regulated than castration sensitive prostate cancer (CSPC). Based on the analysis of m⁶A-sequencing data, we found m⁶A modification level of HRas proto-oncogene, GTPase (HRAS) and mitogen-activated protein kinase kinase 2 (MEK2 or MAP2K2) were enhanced in CRPC. Specifically, tissue microarray analysis and molecular biology experiments confirmed that METTL3, an m⁶A “writer” up-regulated after castration, activated the ERK pathway to contribute to malignant phenotype including ADT resistance, cell proliferation and invasion. We revealed that METTL3-mediated ERK phosphorylation by stabilizing the transcription of HRAS and positively regulating the translation of MEK2. In the Enzalutamide-resistant (Enz-R) C4-2 and LNCap cell line (C4-2^R, LNCap^R) established in the current study, the ERK pathway was confirmed to be regulated by METTL3. We also found that applying antisense oligonucleotides (ASOs) to target the METTL3/ERK axis can restore Enzalutamide resistance in vitro and in vivo. In conclusion, METTL3 activated the ERK pathway and induced the resistance to Enzalutamide by regulating the m⁶A level of critical gene transcription in the ERK pathway.

Renal fibrosis is a common characteristic and the final pathological mechanism of chronic kidney disease (CKD). Although CKD remains incurable, inhibition of renal fibrosis is beneficial to inhibit the CKD process. Relaxin alleviates renal fibrosis in some experimental models, but its mechanism remains unclear. In the following, we studied the regulatory effect of relaxin on epithelial-mesenchymal transition (EMT) after unilateral ureteral obstruction (UUO). Our results demonstrate that relaxin could downregulate Wnt/β-catenin signaling and decrease EMT, thus protecting against loss of transporters in tubular epithelial cells (TECs) and abrogate renal interstitial fibrosis following UUO. We confirmed that relaxin can downregulate Wnt/β-catenin signaling and decrease EMT in NRK52E, thus abrogating G2 cell cycle arrest in vitro experiments. Therefore, a novel mechanism by which relaxin is antifibrotic is that relaxin regulates the EMT program of TECs via Wnt/β-catenin signaling pathway. The inhibition of EMT contributes to protecting the functional capabilities of TECs and promoting the regeneration of TECs.

Background: Clear cell renal cell carcinoma (ccRCC) is essentially a metabolic disorder characterized by reprogramming of several metabolic pathways. Acyl-coenzyme A thioesterases (ACOTs) are critical enzymes involved in fatty acid metabolism; however, the roles of ACOTs in ccRCC remain unclear. This study explored ACOTs expressions and their diagnostic and prognostic values in ccRCC.Methods: Three online ccRCC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were utilized to measure the expressions of ACOTs in paired normal and tumor tissues. Receiver operating characteristic (ROC) curves were depicted to assess the diagnostic values of ACOTs in ccRCC. Quantitative real-time PCR and immunohistochemical analysis were performed to validate the ACOT11 expression in ccRCC cell lines and clinical samples. Survival curves and Cox regression analysis were used to evaluate the predictive values of ACOTs in clinical outcome of ccRCC patients. Functional enrichment analyses and correlation analysis were carried out to predict the potential roles of ACOT8 in tumorigenesis and progression of ccRCC.Results: ACOT1/2/8/11/13 were found to be significantly downregulated in ccRCC samples. In particular, ACOT11 was decreased in almost every matched normal-tumor pair, and had extremely high diagnostic value as shown by ROC curve analysis (AUC = 0.964). The expression of ACOT11 was further verified in ccRCC cell lines and clinical samples at mRNA and protein levels. Furthermore, clinical correlation analysis and survival analysis indicated that ACOT8 was correlated with disease progression and was an independent predictor of unfavorable outcome in ccRCC. Moreover, functional analyses suggested potential roles of ACOT8 in the regulation of oxidative phosphorylation (OXPHOS), and correlation analysis revealed an association between ACOT8 and ferroptosis-related genes in ccRCC.Conclusion: Our study revealed that ACOT11 and ACOT8 are promising biomarkers for diagnosis and prognosis of ccRCC, respectively, and ACOT8 may affect ccRCC development and progression through the regulation of OXPHOS and ferroptosis. These findings may provide new strategies for precise diagnosis and personalized therapy of ccRCC.