TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia.

The clinical treatment of AML is dominated by "7 + 3" therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.

Neutrophil gelatinase-associated lipocalin as predictor of acute kidney injury requiring renal replacement therapy: A systematic review and meta-analysis.

Background: Patients with severe acute kidney injury (AKI) may require renal replacement therapy (RRT), such as hemodialysis and peritoneal dialysis. Neutrophil gelatinase-associated lipocalin (NGAL) is a sensitive indicator for early diagnosis and recognition of AKI; however, its predictive value of AKI-associated need for RRT needs further evaluation. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, relevant articles were systematically searched and selected from seven databases. The random effects model was applied to evaluate the predictive performance of NGAL for AKI requiring RRT. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of each included study. Results: A total of 18 studies including 1,787 patients with AKI and having an average NOS score of 7.67 were included in the meta-analysis. For plasma/serum NGAL, the pooled sensitivity and specificity with corresponding 95% confidence interval (CI) were 0.75 (95% CI: 0.68-0.81) and 0.76 (95% CI: 0.70-0.81), respectively. The pooled positive likelihood ratio (PLR) was 2.9 (95% CI: 2.1-4.1), and the pooled negative likelihood ratio (NLR) was 0.34 (95% CI: 0.25-0.46). Subsequently, the pooled diagnostic odds ratio (DOR) was 9 (95% CI: 5-16) using a random effects model, and the area under the curve (AUC) of summary receiver operating characteristic to summarize predictive accuracy was 0.82 (95% CI: 0.79-0.85). For urine NGAL, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC values were 0.78 (95% CI: 0.61-0.90), 0.77 (95% CI: 0.65-0.85), 3.4 (95% CI: 2.4-4.8), 0.28 (95% CI: 0.15-0.52), 12 (95% CI: 6-24), and 0.84 (95% CI: 0.80-0.87), respectively. Conclusion: Plasma/serum and urine NGAL levels performed comparably well in predicting AKI requiring RRT. Our findings suggested that NGAL is an effective predictive biomarker for the AKI-associated need for RRT. Nevertheless, more pieces of high-quality evidence and future trials with larger sample sizes are needed for further improvement of patient outcomes. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022346595], identifier [CRD42022346595].

C12orf59 Promotes Esophageal Squamous Cell Carcinoma Progression via YAP-Mediated Epithelial-Mesenchymal Transition.

C12orf59 is a novel gene widely expressed in diverse normal human tissues. Aberrant expression of C12orf59, which is involved in tumor progression, has been reported in a few types of cancer. However, its expression and biological function in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that the mRNA and protein levels of C12orf59 were prominently higher in both tumor tissues and most ESCC cell lines. Functionally, C12orf59 overexpression promoted ESCC cell proliferation, migration and invasion, whereas C12orf59 depletion worked oppositely. Mechanistically, C12orf59 exerted its oncogenic function through the induction of epithelial-mesenchymal transition (EMT) of ESCC cells, which relied on Yes-associated protein (YAP) dephosphorylation and nuclear translocation. Constitutively active YAP further facilitated cell migration, invasion and EMT induced by enforced C12orf59 overexpression. On the contrary, increased cell motility and EMT caused by enforced C12orf59 overexpression were dramatically repressed upon YAP inactivation by verteporfin. Thus, we conclude that YAP activation driven by C12orf59 contributes to the malignancy of ESCC through EMT and that targeting drugs for C12orf59 combined with YAP inhibitor may be a potential therapeutic strategy for ESCC.

Identification of a Novel Epigenetic Signature CHFR as a Potential Prognostic Gene Involved in Metastatic Clear Cell Renal Cell Carcinoma.

Metastasis is the main cause of clear cell renal cell carcinoma (ccRCC) treatment failure, and the key genes involved in ccRCC metastasis remain largely unknown. We analyzed the ccRCC datasets in The Cancer Genome Atlas database, comparing primary and metastatic ccRCC tumor records in search of tumor metastasis-associated genes, and then carried out overall survival, Cox regression, and receiver operating characteristic (ROC) analyses to obtain potential prognostic markers. Comprehensive bioinformatics analysis was performed to verify that the checkpoint with forkhead associated and ring finger domains (CHFR) gene is a reliable candidate oncogene, which is overexpressed in ccRCC metastatic tumor tissue, and that high expression levels of CHFR indicate a poor prognosis. A detailed analysis of the methylation of CHFR in ccRCC tumors showed that three sites within 200 bp of the transcription initiation site were significantly associated with prognosis and that hypomethylation was associated with increased CHFR gene expression levels. Knockdown of CHFR in ccRCC cells inhibited cell proliferation, colony formation, and migration ability. In summary, our findings suggest that the epigenetic signature on CHFR gene is a novel prognostic feature; furthermore, our findings offer theoretical support for the study of metastasis-related genes in ccRCC and provided new insights for the clinical treatment of the disease.

C19orf10 promotes malignant behaviors of human bladder carcinoma cells via regulating the PI3K/AKT and Wnt/ß-catenin pathways.

Background: Chromosome 19 open reading frame 10 (C19orf10) is a myocardial repair mediator overexpressed in hepatocellular carcinoma. However, its function and clinical value in bladder cancer (BC) have not been reported. This study aimed to investigate the role of C19orf10 in BC progression and explore underlying mechanisms. Methods: C19orf10 expression in BC tissues and human BC cell lines was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The correlation between the C19orf10 protein levels determined by immunohistochemical staining and the clinicopathological characteristics of 192 BC patients was evaluated. BC cell lines SW780, J82 and UMUC-3 were transfected with small interfering RNA (siRNA) targeting C19orf10 or plasmids overexpressing C19orf10. Cell proliferation, migration and invasion were measured by Cell Counting Kit-8, Colony formation, EdU incorporation and Transwell assays. The effect of small hairpin RNA (shRNA)-mediated stable C19orf10 knockdown on tumor formation was assessed in a xenograft mouse model. The expressions of epithelial-mesenchymal transition (EMT) markers, PI3K/AKT and Wnt/ß-catenin signaling pathways-related molecules were determined by western blot assay. Results: C19orf10 was significantly upregulated in the BC tissues and a panel of human BC cell lines. High expression of C19orf10 was positively associated with malignant behaviors in BC. C19orf10 knockdown inhibited cell proliferation, migration, and invasion in SW780 and J82 cells, while C19orf10 overexpression in UMUC-3 cells resulted in opposite effects. In addition, C19orf10 silence in SW780 cells suppressed tumor growth in xenograft mice. Moreover, C19orf10 promotes the malignant behaviors and EMT of human bladder carcinoma cells via regulating the PI3K/AKT and Wnt/ß-catenin pathways. Conclusion: C19orf10 is overexpressed in BC and functions as an oncogenic driver that promotes cell proliferation and metastasis, and induces EMT of BC cells via mechanisms involving activation of the PI3K/AKT and Wnt/ß-catenin pathways. This study provides valuable insight on targeting C19orf10 for BC treatment.

PAPP-A functions as a tumor suppressor and is downregulated in renal cell carcinoma.

Pregnancy-associated plasma protein A (PAPP-A) is a proteolytic enzyme produced by the placenta. The expression and role of PAPP-A in renal cell carcinoma (RCC) remain elusive. The aim of this study was to investigate the role and the molecular mechanisms of PAPP-A in RCC. Initially, we evaluated the expression of PAPP-A in samples from patients with RCC and cell lines by quantitative PCR, western blot and immunohistochemical staining, and examined the role of PAPP-A in RCC cells by cell viability, colony formation and Transwell assays. Next, we investigated the molecular mechanisms regulating the tumor suppressor function of PAPP-A. Our results demonstrated that PAPP-A is expressed at low levels in RCC tissues and cells. Clinical data analysis revealed a significant correlation between PAPP-A expression and RCC-related death (P < 0.0115). Overexpression of PAPP-A inhibited viability, proliferation, migration and invasion of RCC cells. Furthermore, PAPP-A overexpression significantly increased phosphorylation of c-Jun N-terminal kinase and decreased the expression of cyclin D1, phosphorylated glycogen synthase kinase-3ß and ß-catenin. This study is the first to report that downregulation of PAPP-A is associated with poor prognosis in patients with RCC. In conclusion, PAPP-A may serve as a novel prognostic marker and potentially as a therapeutic target in patients with RCC.

miR-216b Post-Transcriptionally Downregulates Oncogene KRAS and Inhibits Cell Proliferation and Invasion in Clear Cell Renal Cell Carcinoma.

BACKGROUND/AIMS: Increasing evidence has shown that miR-216b plays an important role in human cancer progression. However, little is known about the function of miR-216b in renal cell carcinoma. METHODS: The expression levels of miR-216b in renal cell carcinoma tissues and cell lines were examined by qRT-PCR. The biological role of miR-216b in renal cell carcinoma proliferation and/or metastasis was examined in vitro and in vivo. The target of miR-216b was identified by a dual-luciferase reporter assay. The expression level of KRAS protein was measured by western blotting. RESULTS: The expression of miR-216b was downregulated in clear cell renal cell carcinoma (ccRCC) cell lines and specimens compared to the adjacent normal tissues. Furthermore, miR-216b can bind to the 3'untranslated region (UTR) of KRAS and inhibit the expression of KRAS through translational repression. The in vitro study revealed that miR-216b attenuated ccRCC cell proliferation and invasion. Furthermore, in vivo study also showed that miR-216b suppressed tumor growth. MiR-216b exerted its tumor suppressor function through inhibiting the KRAS-related MAPK/ERK and PI3K/AKT pathways. CONCLUSION: Our findings provide, for the first time, significant clues regarding the role of miR-216b as a tumor suppressor by targeting KRAS in ccRCC.