The LMR-SSIGN-MAPS model predicts disease-free survival in patients with localized clear cell renal cell carcinoma.

Introduction: Prediction models are increasingly being used to predict outcomes after surgery, and such a model would be a precious tool for patients with clear cell renal cell carcinoma (ccRCC) after surgery. Aim: To develop a comprehensive model for predicting disease-free survival (DFS) in patients with localized ccRCC. Material and methods: In a retrospective analysis of 612 patients, least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to identify significant predictors, and then risk factors were used to construct a prognostic model. Harrell's concordance index (C-index) was used to assess the accuracy of the model. Results: The lymphocyte-to-monocyte ratio (LMR), Mayo Clinic stage, size, grade, necrosis score (SSIGN), and Mayo adhesive probability score (MAPS) were the significant risk factors screened by LASSO Cox regression and reconfirmed by multivariate Cox regression analysis in 44 variables. Then a model was constructed by combining the LMR, SSIGN, and MAPS. The C-index of the LMR-SSIGN-MAPS model was greater than the SSIGN score alone. Kaplan-Meier survival analysis demonstrated a significant association between higher LMR-SSIGN-MAPS score and poorer DFS. Conclusions: The LMR-SSIGN-MAPS model, which consists of preoperative inflammation biomarkers, a perinephric adipose tissue image-based scoring system, and pathological features, showed the strengths of easy-to-use and high predictability and might also be used as a promising prognosis model in predicting DFS for patients with localized ccRCC.

Cuproptosis related gene PDHB is identified as a biomarker inversely associated with the progression of clear cell renal cell carcinoma.

BACKGROUND: Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC. RESULTS: The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells. CONCLUSION: Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.

Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT/mTOR pathway in prostate cancer.

Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first-line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol-CuCl2 , as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol-CuCl2 and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol-CuCl2 could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol-CuCl2 induced cell death and inhibited the growth of prostate cancer cells relying on copper ions-induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S-acetyltransferase (DLAT) was involved in cuproptosis-enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis-regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.

DDX58 expression promotes inflammation and growth arrest in Sertoli cells by stabilizing p65 mRNA in patients with Sertoli cell-only syndrome.

Sertoli cell -only syndrome (SCOS) is a type of testicular pathological failure that causes male infertility and no effective treatment strategy, is available for this condition. Moreover, the molecular mechanism underlying its development remains unknown. We identified DExD/H-Box helicase 58 (DDX58) as a key gene in SCOS based on four datasets of testicular tissue samples obtained from the Gene Expression Synthesis database. DDX58 was significantly upregulated in SCOS testicular Sertoli cells. Moreover, high expression of DDX58 was positively correlated with the expression of several testicular inflammatory factors, such as IL -1ß, IL-18, and IL-6. Interestingly, DDX58 could be induced in the D-galactose (D-gal)-stimulated TM4 cell injury model. Whereas silencing of DDX58 inhibited D-gal -mediated p65 expression, inflammatory cytokine release, and growth arrest. Mechanistically, we found that DDX58 acts as an RNA-binding protein, which enhances p65 expression by promoting mRNA stability. Furthermore, p65 gene silencing decreased the expression of inflammatory cytokines and inhibition of cell growth in D-gal-induced cells. In conclusion, our findings demonstrate that DDX58 promotes inflammatory responses and growth arrest in SCOS Sertoli cells by stabilizing p65 mRNA. Accordingly, the DDX58/p65 regulatory axis might be a therapeutic target for SCOS.

TREM2 as an independent predictor of poor prognosis promotes the migration via the PI3K/AKT axis in prostate cancer.

OBJECTIVE: Prostate adenocarcinoma (PRAD) is one of the most common cancers, with high morbidity and mortality. Triggering receptors expressed on myeloid cells 2 (TREM2) is upregulated in various malignancies, however its effect on PRAD remains unknown. This study aimed to investigate the prognostic value of TREM2 in PRAD. METHODS: PRAD samples were collected from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), Oncomine, and the Human Protein Atlas (HPA) to analyze the differences in TREM2 expression between normal and tumor tissues. The influence of TREM2 on the clinicopathological characteristics and its prognostic value were evaluated using the Kaplan-Meier curve, Cox regression analysis, ROC (receiver operating characteristic) plot, and nomogram. Gene Ontology (GO), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) were conducted to screen biological functions and pathways. The relationship between TREM2 and tumor microenvironment (TME) characteristics was explored. The TREM2 expression in PRAD specimens and cell lines was assessed by immunohistochemistry staining and western blot. TREM2-specific siRNAs were used to evaluate the effects of TREM2 on cell function. RESULTS: TREM2 was upregulated and positively associated with poor clinicopathologic characteristics. Overexpression of TREM2 is an independent biomarker for the prognosis of PFI (progression-free interval). Moreover, TREM2 expression was positively correlated with various TME characteristics. Knockdown of TREM2 inhibited the migration of PRAD cell lines via the PI3K/AKT axis. CONCLUSION: High TREM2 expression may represent a novel diagnostic and prognostic biomarker and serve as a potential target gene for PRAD therapy.