Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an ...essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe
efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Circular RNAs (circRNAs) represent a class of non-coding RNAs that play a vital role in modulating gene expression and several pathological responses. However, the expression profile and function of ...circRNAs in triple-negative breast cancer (TNBC) remain unknown. In the current study, we investigated the expression profile of human circRNAs in TNBC tissues and identified circEPSTI1 (hsa_ circRNA_000479) as a significantly upregulated circRNA.
We performed circular RNA microarray assays to screen circular RNA expression profiles of TNBC and further investigated circEPSTI1. We observed the effect of circEPSTI1 on proliferation, clonal formation and apoptosis in TNBC by knocking downcircEPSTI1 in three TNBC cell lines. Based on the MRE analysis and luciferase reporter assay, we found that circEPSTI1 binds to miRNAs as a miRNA sponge and the co-target genes of miRNAs. We performed xenograft experiments in mice to confirm our findings. We evaluated circEPSTI1 levels in 240 TNBC patients by ISH.
Knockdown of circEPSTI1 inhibits TNBC cell proliferation and induces apoptosis.
and
experiments indicated that circEPSTI1 binds to miR-4753 and miR-6809 as a miRNA sponge to regulate BCL11A expression and affect TNBC proliferation and apoptosis. High levels of circEPSTI1 correlate with reduced survival in TNBC patients.
The circEPSTI1-miR-4753/6809-BCL11A axis affect the proliferation and apoptosis of triple-negative breast cancer through the mechanism of competing endogenous RNAs (ceRNA). In addition, our results identify circEPSTI1 as an independent prognostic marker for survival in patients with TNBC.
The purpose of this study was to investigate the clinicopathologic significance and potential role of miR-200b and miR-200c in the development and progression of gastric cancer.
We examined miR-200b ...and miR-200c expression in 36 paired normal and stomach tumor specimens, as well as gastric cancer cell lines, by quantitative real-time PCR. In addition, miR-200b and miR-200c were detected by ISH using gastric cancer tissue microarrays, and the association between miR-200b and miR-200c levels and clinicopathologic factors and prognosis were analyzed. A luciferase assay was conducted for target evaluation. The functional effects of miR-200b and miR-200c on gastric cancer cells were validated by a cell proliferation assay and cell invasion and migration assays.
miR-200b and miR-200c were downregulated in the gastric cancer specimens and cell lines tested. miR-200b and miR-200c levels were significantly correlated with the clinical stage, T stage, lymph node metastasis, and survival of patients. Ectopic expression of miR-200b and miR-200c impaired cell growth and invasion. In addition, when overexpressed, miR-200b and miR-200c commonly directly targeted DNMT3A, DNMT3B, and SP1 (a transactivator of the DNMT1 gene), which resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at the protein level. This effect, in turn, led to a decrease in global DNA methylation and reexpression of p16, RASS1A1, and E-cadherin via promoter DNA hypomethylation.
Our findings suggest that miR-200b and miR-200c, as valuable markers of gastric cancer prognosis, may be a promising approach to human gastric cancer treatment.
Circular RNA CDR1as/ciRS-7 functions as an oncogenic regulator in various cancers. However, there has been a lack of systematic and comprehensive analysis to further elucidate its underlying role in ...cancer. In the current study, we firstly performed a bioinformatics analysis of CDR1as among 868 cancer samples by using RNA-seq datasets of the MiOncoCirc database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), CIBERSORT, Estimating the Proportion of Immune and Cancer cells (EPIC), and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were applied to investigate the underlying functions and pathways. Functional enrichment analysis suggested that CDR1as has roles associated with angiogenesis, extracellular matrix (ECM) organization, integrin binding, and collagen binding. Moreover, pathway analysis indicated that it may regulate the TGF-β signaling pathway and ECM-receptor interaction. Therefore, we used CIBERSORT, EPIC, and the ESTIMATE algorithm to investigate the association between CDR1as expression and the tumor microenvironment. Our data strongly suggest that CDR1as may play a specific role in immune and stromal cell infiltration in tumor tissue, especially those of CD8+ T cells, activated NK cells, M2 macrophages, cancer-associated fibroblasts (CAFs) and endothelial cells. Generally, systematic and comprehensive analyses of CDR1as were conducted to shed light on its underlying pro-cancerous mechanism. CDR1as regulates the TGF-β signaling pathway and ECM-receptor interaction to serve as a mediator in alteration of the tumor microenvironment.
Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in ...triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.
Abstract Objectives Although dyslipidemia has been documented to be associated with several types of cancer including breast cancer, it remains uncertainty the prognostic value of serum lipid in ...breast cancer. The purpose of this study is to evaluate the association between the preoperative plasma lipid profile and the prognostic of breast cancer patients. Methods The levels of preoperative serum lipid profile (including cholesterol CHO, Triglycerides TG, high-density lipoprotein-cholesterol HDL-C, low-density lipoprotein-cholesterol LDL-C, apolipoprotein A-I ApoAI, and apolipoprotein B ApoB) and the clinical data were retrospectively collected and reviewed in 1044 breast cancer patients undergoing operation. Kaplan-Meier method and the Cox proportional hazards regression model were used in analyzing the overall survival OS and disease-free survival DFS. Results Combining the receiver-operating characteristic and Kaplan-Meier analysis , w e found that preoperative lower TG and HDL-C level were risk factors of breast cancer patients. In multivariate analyses, a decreased HDL-C level showed significant association with worse OS (HR: 0.528; 95% CI: 0.302–0.923; P = 0.025), whereas a decreased TG level showed significant association with worse DFS (HR: 0.569; 95% CI: 0.370–0.873; P = 0.010). Conclusions Preoperative serum levels of TG and HDL-C may be independent factor to predict outcome in breast cancer patient.
Chemokines, which are chemotactic inflammatory mediators involved in controlling the migration and residence of all immune cells, are closely associated with brain inflammation, recognized as one of ...the potential processes/mechanisms associated with cognitive impairment. We aim to determine the chemokines which are significantly altered in Alzheimer's disease (AD) and mild cognitive impairment (MCI), as well as the respective effect sizes, by performing a meta-analysis of chemokines in cerebrospinal fluid (CSF) and blood (plasma or serum).
We searched three databases (Pubmed, EMBASE and Cochrane library) for studies regarding chemokines. The three pairwise comparisons were as follows: AD vs HC, MCI vs healthy controls (HC), and AD vs MCI. The fold-change was calculated using the ratio of mean (RoM) chemokine concentration for every study. Subgroup analyses were performed for exploring the source of heterogeneity.
Of 2338 records identified from the databases, 61 articles comprising a total of 3937 patients with AD, 1459 with MCI, and 4434 healthy controls were included. The following chemokines were strongly associated with AD compared with HC: blood CXCL10 (RoM, 1.92, p = 0.039), blood CXCL9 (RoM, 1.78, p < 0.001), blood CCL27 (RoM, 1.34, p < 0.001), blood CCL15 (RoM, 1.29, p = 0.003), as well as CSF CCL2 (RoM, 1.19, p < 0.001). In the comparison of AD with MCI, there was significance for blood CXCL9 (RoM, 2.29, p < 0.001), blood CX3CL1 (RoM, 0.77, p = 0.017), and blood CCL1 (RoM, 1.37, p < 0.001). Of the chemokines tested, blood CX3CL1 (RoM, 2.02, p < 0.001) and CSF CCL2 (RoM, 1.16, p = 0.004) were significant for the comparison of MCI with healthy controls.
Chemokines CCL1, CCL2, CCL15, CCL27, CXCL9, CXCL10, and CX3CL1 might be most promising to serve as key molecular markers of cognitive impairment, although more cohort studies with larger populations are needed.
Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells ...(MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.
Our study aims to construct a prognosis‐related immune phenotype classifier for predicting clinical prognosis and immune activity in triple‐negative breast cancer (TNBC). A total of 237 patients with ...TNBC from Sun Yat‐sen University Cancer Center (SYSUCC) and 533 patients with TNBC from public datasets were included in our study. A stromal immune quantified index was generated with a LASSO Cox regression model based on five prognosis‐related immune cells evaluated by CIBERSORT or IHC and was used to determine immune phenotypes. Immune features were evaluated in the samples before chemotherapy. A total of 119 patients in the SYSUCC training cohort were classified into immune Phenotypes A and B according to the density of stromal CD4+ T cells, γδ T cells, monocytes, M1 macrophages and M2 macrophages. Phenotype A predicted better survival than Phenotype B, and the classification was further validated in the testing cohort of 118 patients and the validation cohort of 533 patients. In the combined cohort, significant differences were found in Phenotype A compared to Phenotype B for the 5‐year overall survival (83.5% vs 65.8%, respectively, P < .01) and the 5‐year disease‐free survival (87.3% vs 76.0%, respectively, P < .01). In Phenotype A, immune‐related pathways were significantly enriched, and a higher level of immune checkpoint molecules, including PD‐L1, PD‐1 and CTLA‐4, could be observed. The immune phenotype classification was an independent prognostic indicator for TNBC and might serve as a potential predictor for immune activity within the tumor microenvironment.
What's new?
Stromal infiltrating immune cells play a crucial role in tumor proliferation, invasion, and metastasis. However, few studies have investigated the prognostic potential of an overall stromal immune‐cell signature in triple‐negative breast cancer (TNBC). Here, the authors developed an immune index that classified patients into two immune phenotypes with different prognoses. Among the stromal infiltrating immune cells in TNBC, CD4+ T cells, γδ T cells, and M1 macrophages predicted a better prognosis, while monocytes and M2 were worse indicators. The classification was an independent prognostic indicator for TNBC and might serve as a potential predictor for the tumor microenvironment immune activity.
To study the effect of weaning age on the gut microbiota diversity in the lambs of Chongming white goats, fresh feces from the lambs weaned at 30, 45, and 60 days of age were collected 3 days after ...weaning at 33, 48, and 63 days of age, for microbial composition analysis by 16S rRNA sequencing. The serum concentrations of lipid metabolites were also investigated at the fecal collection dates. Serum and feces from the ewe-reared groups at 33, 48, and 63 days of age were used as controls. The alpha diversity increased significantly after weaning and with the aging of the lambs. Levels of
Ruminococcaceae
,
Lachnospiraceae
, and
Ruminococcus
varied significantly according to the weaning treatment in lambs (
P
< 0.05). Butyrate-producing gut bacteria such as
Ruminococcaceae
_UCG-010,
Ruminococcaceae
_UCG-013,
Ruminococcaceae
_UCG-014,
Ruminococcaceae
_UCG-005,
Ruminococcaceae
_UCG-002,
Lachnospiraceae
_AC2044_group, and
Lachnospiraceae
_NK4B4 were identified as significantly increased genera (
P
< 0.05) in the feces of weaned Chongming white lambs. Additionally, the abundance of fiber degradation–associated bacteria including
Ruminococcaceae
_UCG-005,
Ruminococcus
_1, and
Ruminococcus
_2 significantly increased with lamb weaning age (
P
< 0.05). Correlation analysis showed that
Lachnospiraceae
_AC2044_group, norank_f__
Bacteroidales
_S24-7_group, and
Ruminococcaceae
_UCG_005 were negatively correlated, and
Lachnoclostridium
was positively correlated with levels of cholesterol, while
Blautia
showed positive correlation with low-density lipoprotein cholesterol in serum samples from weaned lambs. This study helped to understand the maturing development of gut microbiota in Chongming white goats under weaning stress.
Key points
•
Effects of weaning age on the gut microbiota diversity in Chongming white goat lambs were studied.
•
Some butyrate-producing gut bacteria were significantly increased after weaned.
•
Correlations of gut microbiota and lipid metabolites were analyzed.
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