YTHDF1 enhances stemness and chemoresistance in triple-negative breast cancer cells by upregulating SIAH2.

Triple-negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer, and chemoresistance is the major determinant of TNBC treatment failure. This study explores the molecular mechanism of TNBC chemoresistance. The Cancer Genome Atlas, breast cancer integrative platform, and GEPIA databases were used to analyze the expression and correlation of YTHDF1 and seven in absentia homology 2 (SIAH2) in breast cancer. Knockdown of YTHDF1 and SIAH2, or overexpression of SIAH2 in vitro and in vivo, was conducted to evaluate the impact of changes in YTHDF1 and SIAH2 expression on TNBC cell proliferation, apoptosis, stemness, drug resistance, and Hippo pathway gene expression. YTHDF1 and SIAH2 were highly expressed in breast cancer patients and TNBC cells. Knockdown of YTHDF1 and SIAH2 significantly inhibited proliferation and stemness and promoted apoptosis and chemosensitivity of TNBC cells. Mechanistically, the knockdown of YTHDF1 inhibited the expression of SIAH2, thereby downregulating the Hippo pathway, which inhibited proliferation and stemness and promoted apoptosis and chemosensitivity of TNBC cells. The current findings revealed the regulatory mechanism of YTHDF1 in TNBC and clarified the role of the YTHDF1/SIAH2 axis in TNBC drug resistance and stemness. This could provide new insights into the vital role of targeting YTHDF1/SIAH2 to suppress drug resistance and stemness in TNBC cells.

Network meta-analysis of different liver protective drugs in the treatment of drug-induced liver injury.

BACKGROUND: Currently, drug-induced liver injury (DILI) has become one of those public issues in society, which has added a huge burden to both the individuals and the society. In the current clinical stage, there are numerous drugs developed to treat this disease, and different drug treatment measures have been proven to achieve certain clinical efficacy in the corresponding randomized controlled trials. However, there are still many therapeutic drugs that have not been directly compared and studied. Therefore, it is difficult to directly compare the effectiveness and safety of various strategies for the treatment of DILI. In this regard, the present study collected the therapeutic efficacy of diverse treatments in DILI in recent years through network meta-analysis, evaluated and screened the existing optimal clinical therapeutic plan, and helped physicians formulate clinical therapeutic plans. METHODS: Databases, including the Chinese Journal Full-text Database, Wanfang Data Journal Paper Resources (Wangfang), VIP Chinese Science and Technology Journal Full-text Database, The Cochrane Library, PubMed, and EMBASE, were searched using keywords from inception to January 2023. Eligible randomized controlled trials were selected in line with eligibility criteria, and mesh meta-analysis of binary variables was carried out using Stata 16 software. CONCLUSION: In combination with alanine aminotransferase, aspartate aminotransferase, and total bilirubin, MI may be the intervention measure for minimizing alanine aminotransferase levels in patients after treatment. Besides, compound glycyrrhizin may be the intervention for minimizing aspartate aminotransferase levels in patients after treatment, and polyene phosphatidylcholine may be the intervention for minimizing total bilirubin levels in patients after treatment. Placebo is the potential intervention that has the least adverse reactions post-treatment, and RT has the second least adverse reactions. Moreover, hepatocyte growth-promoting factors may be the most effective intervention after treatment. RESULTS: To sum up, the present work compared the clinical effects of 13 liver protective drugs through meta-analysis and provided a systematic understanding of commonly used drugs for the treatment of DILI in clinical practice.

Propofol and Sevoflurane Alleviate Malignant Biological Behavior and Cisplatin Resistance of Xuanwei Lung Adenocarcinoma by Modulating the Wnt/ß-catenin Pathway and PI3K/AKT Pathway.

BACKGROUND: Recent studies have shown that propofol and sevoflurane, two common anesthetics, can prevent tumor development. The prevalence of lung adenocarcinoma in China is highest in Yunnan Xuanwei, and many patients with lung cancer in this area are often resistant to platinum-based treatments. OBJECTIVE: The objective of the study was to investigate the effects of propofol and sevoflurane on malignant biological behavior and cisplatin resistance of Xuanwei lung adenocarcinoma. METHODS: Herein, XWLC-05/R, a cisplatin-resistant cell line of XWLC-05 cells from Xuanwei lung adenocarcinoma, was constructed. The XWLC-05 cells and XWLC-05/R cells were treated with propofol and sevoflurane singly or as a combination and subjected to CCK-8 assay, clone formation tests, and flow cytometry analysis to assess the proliferation level of cells. The morphology and number of apoptotic bodies in XWLC-05 cells and XWLC-05/R were examined with a transmission electron microscope. The ANNEXIN V-FITC/PI and transwell assays were performed to evaluate apoptosis, invasion, and migration of the cells. Subsequently, we constructed a Xuanwei lung adenocarcinoma xenograft model to investigate the effects of propofol and sevoflurane on the tumorigenicity of XWLC-05 cells in vivo. RESULTS: Treatment with propofol and sevoflurane significantly inhibited proliferation, invasion, migration, and induced apoptosis of XWLC-05 and XWLC-05/R cells. These effects were more pronounced when propofol and sevoflurane were co-incubated with the cells. Moreover, both propofol and sevoflurane significantly inhibited Wnt/ß- catenin and PI3K/AKT pathways. Moreover, the two drugs effects suppressed the malignant biological behavior of XWLC-05 cells and XWLC-05/R cells, and this effect was counteracted by 740Y-P (PI3K/AKT pathway activator) and Wnt pathway activator 1 (Wnt/ß-catenin pathway activator). In vivo experiments confirmed that propofol and sevoflurane alleviated the tumorigenicity of XWLC-05 cells. CONCLUSIONS: In summary, this study shows, for the first time, that propofol and sevoflurane decrease the proliferation, invasion, migration and induce apoptosis of XWLC-05 cells and XWLC-05/R cells by impeding the Wnt/ß-catenin and PI3K/AKT signaling pathways, thereby alleviating the development of Xuanwei lung adenocarcinoma in vivo. Moreover, these effects are more pronounced when the two drugs are combined.

Pivotal models and biomarkers related to the prognosis of breast cancer based on the immune cell interaction network.

The effect of breast cancer heterogeneity on prognosis of patients is still unclear, especially the role of immune cells in prognosis of breast cancer. In this study, single cell transcriptome sequencing data of breast cancer were used to analyze the relationship between breast cancer heterogeneity and prognosis. In this study, 14 cell clusters were identified in two single-cell datasets (GSE75688 and G118389). Proportion analysis of immune cells showed that NK cells were significantly aggregated in triple negative breast cancer, and the proportion of macrophages was significantly increased in primary breast cancer, while B cells, T cells, and neutrophils may be involved in the metastasis of breast cancer. The results of ligand receptor interaction network revealed that macrophages and DC cells were the most frequently interacting cells with other cells in breast cancer. The results of WGCNA analysis suggested that the MEblue module is most relevant to the overall survival time of triple negative breast cancer. Twenty-four prognostic genes in the blue module were identified by univariate Cox regression analysis and KM survival analysis. Multivariate regression analysis combined with risk analysis was used to analyze 24 prognostic genes to construct a prognostic model. The verification result of our prognostic model showed that there were significant differences in the expression of PCDH12, SLIT3, ACVRL1, and DLL4 genes between the high-risk group and the low-risk group, which can be used as prognostic biomarkers.

Bioinformatics Analysis of the Characteristics and Correlation of m6A Methylation in Breast Cancer Progression.

Growing cutting-edge study has demonstrated the RNA m6A methylation's critical role in regulating tumorigenesis and progression all over the world, while it is still a mystery whether RNA m6A methylation has a positive impact on breast cancer treatment. In this article, we utilize bioinformatics to analyze three data sets including TCGA-BRCA, GSE96058, and GSE25066 and discover that breast cancer samples could be divided into 4 subtypes, which are quiescent, m6A methylation, protein-binding, and mixed, clarified by the expression level of m6A-related genes. R-survival analysis results also prove that the survival rate of breast cancer samples of the four subtypes significantly varies and remarkable differences in the number of exons' skip among the four subtypes can be seen according to the analysis of breast cancer gene expression characteristics. The degree of TP53 mutation and copy number loss is most obvious in the protein-binding subtype when it comes to tumor driver genes. Among the DNA damage repair genes, there is a sharp increase in the copy number of RAD54B of the protein-binding subtype, but fewer mutations in other DNA damage repair-related genes and copy number deletion is everywhere. Results of m6A methylation influencing on the proportion of infiltrated immune cells also indicate significant differences of the four m6A subgroups in macrophages M0 and mast cells resting which are closely correlated to patient prognosis. In addition, findings of the highest tumor stemness index and the lowest in the m6A methylated type in breast cancer samples can prove the critical role of the high expression of m6A reader protein in the progression of breast cancer.

Demethylation of HACE1 gene promoter by propofol promotes autophagy of human A549 cells.

Propofol (2,6-diisopropylphenol) is one of the most commonly used intravenous anesthetics and possesses a number of non-anesthetic effects, including antitumor function. The aim of the present study was to elucidate the antitumor molecular mechanism of propofol on A549 and H1299 cells. A549 and H1299 cells were treated in the presence or absence of different concentrations (0, 60 or 120 µmol) of propofol for different durations (0, 24, 48 or 72 h), and proliferation was detected by MTT and colony formation assays; the protein levels of optineurin (OPTN) ubiquitination, HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), methyl-CpG binding domain protein 3 (MBD3) and Microtubule-associated protein 1A/1B-light chain 3 were detected by immunoblotting or quantitative (q)PCR; the methylation state of the HACE1 gene promoter was detected by bisulfite DNA sequencing; and binding of MBD3 on HACE1 gene promoter was detected by chromatin immunoprecipitation-qPCR. Propofol inhibited proliferation of A549 and H1299 cells and promoted HACE1-OPTN axis-mediated selective autophagy activity by increasing the protein expression levels of HACE1 via demethylating its promoter region. Furthermore, propofol promoted expression levels of MBD3 and binding to the -1,000 to -1 bp (transcription start site) region of HACE1 gene promoter. MBD3-knockdown experiments indicated that propofol inhibited proliferation of A549 cells in a MBD3-dependent manner. Thus, the findings of the present study provided a potential antitumor molecular mechanism mediated by propofol.