The ubiquitin-proteasome system influences cancer progression through multiple mechanisms. Due to the extensive proteasomal modifications observed in cancer tissues, ubiquitination is closely related to various biological functions with cancer. However, the roles of ubiquitin-related genes (UbRGs) in breast cancer (BC) have not been thoroughly investigated. In this study, we retrieved 763 reliable UbRGs and identified a potential prognostic signature for breast cancer patients. Additionally, we analyzed eight overall survival-associated UbRGs using univariate Cox proportional hazard regression in the Cancer Genome Atlas (TCGA) database. Subsequently, we used Lasso-Cox risk regression analysis to generate prognostic characteristics of UbRGs associated with overall survival (OS), validated in an external cohort (GSE158309). Next, we compared differences in tumor microenvironment and drug sensitivity between subgroups, describing the potential impact of UbRGs on the landscape of the tumor immune microenvironment and their predictive significance for therapeutic resistance to different strategies. Furthermore, a nomogram model containing eight genes, histology, subtype, T status, N status, and the American Joint Committee on Cancer (AJCC) stage was constructed. Finally, in vitro and in vivo experiments validated the effects of FBXL6 and PDZRN3 on breast cancer development. In conclusion, we demonstrate that ubiquitin-related genes are closely associated with breast cancer prognosis, immune environment, and drug sensitivity. Our results offer a new insight into breast cancer treatment.

Background: Glioblastoma multiforme (GBM) is one of the most common brain malignancies characterized by an inflammatory microenvironment and metabolic reprogramming. This study aims to investigate the causal relationship between inflammatory factors (IFs) and GBM, as well as the potential mediating effects of specific plasma metabolites. Methods: We used a bidirectional two-sample Mendelian randomization (MR) approach to investigate the causal associations between 91 IFs and GBM. We employed a two-step MR technique to identify significant mediators in this relationship, followed by a mediation analysis to explore and quantify the mediating effects of specific metabolites on the causal relationship between IFs and GBM. In vitro experiments were conducted to verify the effects of specific IF and metabolite on GBM cells. The response of cells to treatment was examined using a series of assays, including colony formation, cell proliferation, and migration assays. Results: Three IFs showed significant associations with GBM. Among them, fibroblast growth factor 21 (FGF21) had a protective effect against GBM [odds ratio (OR): 0.42; 95% confidence interval (CI): 0.25, 0.71; p=1.00×10-3]. There was no strong evidence that genetically predicted GBM had an effect on FGF21 (OR: 1.04; 95% CI: 0.83, 1.31; p = 0.692). Mediation analysis identified 3-methoxytyrosine (3-MTyr) level (mediation effect of 11.50%) as a significant intermediary. The in vitro study demonstrated that FGF21 inhibited proliferation and migration in GBM cells, whereas 3-MTyr exerted the opposite effects. Conclusion: FGF21 was causally associated with a reduced risk of GBM, and this relationship is partially mediated by 3-MTyr. This identified regulatory network offers a novel avenue for further research into the pathogenic mechanisms of GBM and provides a theoretical foundation for the development of relevant therapeutic regimens.

Background: Relevant studies have demonstrated that plasma metabolites and immune cell characteristics are closely related to colorectal cancer (CRC). However, the causal relationship among these factors remains unclear, particularly regarding whether immune cell traits mediate the causal link between plasma metabolites and CRC. Methods: This study employed a two-step, two-sample Mendelian randomization (MR) using summary data from genome-wide association studies (GWAS) to assess causal associations between 1,400 plasma metabolites, 731 immune cell traits, and CRC. Additionally, it evaluated the mediating effect of immune cell traits and utilized single-cell RNA sequencing (scRNA-seq) to analyze immune cells infiltration in CRC, assess their metabolic functional changes and their interactions with CRC cells. Results: Univariable two-sample MR analysis revealed causal relationships between 49 plasma metabolites and CRC, as well as between 36 immune cell traits and CRC. Two-step MR analysis revealed that two plasma metabolites (Sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1) and 16α-hydroxy-DHEA-3-sulfate) influence CRC through two immune cell traits (SSC-A on CD14+ monocyte and CD3 on CD28- CD8+ T cell). Among these, SSC-A on CD14+ monocyte exhibited the highest mediating effect proportion, at 11.723%. scRNA-seq analysis further confirmed the increased infiltration of CD28- CD8+ T cells and CD14+ monocytes in CRC, along with upregulated sphingolipid metabolism and steroid biosynthesis. These cells were also found to interact with CRC cells, contributing to tumor initiation and progression. Conclusion: This study provides new evidence for the causal relationship between plasma metabolites and CRC, and it identifies immune factors with potential mediating roles. These findings offer new insights for further exploration of the mechanisms underlying the development of CRC.

Endometrial carcinoma (EC) is the most common malignancies of the female reproductive system in developed countries and areas. Ultrasound-guided and hysteroscopic samplings are commonly used to diagnose EC. However, clinicians question their diagnostic efficacy and the associated patient discomfort. DNA methylation is the widely studied epigenetic alteration in human tumors, and tumor screening and diagnosis. This review summarized common methods for collecting clinical samples for methylation testing. Furthermore, we analyzed the diagnostic evaluation indices of different methylation marker assays in clinical diagnosis and discussed the challenges of methylation testing in the future application of EC diagnosis.

Prostate cancer is the most common malignant tumor in male genitourinary system. The incidence of prostate cancer ranks the first among all male malignant tumors worldwide, and the mortality rate ranks the second among all male malignant tumors. Prostate stem cells are heterogeneous subsets with the function of self-regeneration and proliferation in the prostate, which can produce all cell lineages that make up the prostate epithelium. At present, the pathogenesis of prostate cancer remains unclear. According to cancer stem cell hypothesis, prostate cancer may be a stem cell disease, which provides a new direction for revealing the pathogenesis of prostate cancer and developing treatment strategy for prostate cancer. In this mini-review, we highlight recent advances in our understanding of the origin, surface molecular markers, signaling pathway and the significance for clinical treatment of prostate cancer stem cells.

Background: Carcinoembryonic antigen related cell adhesion molecule-1 (CEACAM1) is a very important intercellular adhesion molecule, and its prognostic relevance to breast cancer (BC), especially basal-like breast cancer (BLBC), remains poorly understood.Methods: CEACAM1 mRNA expression data for BC were sourced from the Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis and Cox regression analysis were used to evaluate the prognostic relationship between CEACAM1 expression and BC. Signaling pathways associated with CEACAM1 were analysed using Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Moreover, cell counting kit-8 (CCK-8), flow cytometry, transwell and wound-healing assays were employed to identify the biological functions of CEACAM1 in BLBC.Results: CEACAM1 was correlated with overall survival (OS) of BLBC patients. Compared with the subgroup with better prognosis, the levels of CEACAM1 mRNA expression were significantly lower in the subgroup of BLBC with poorer prognosis. Both univariate and multivariate Cox regression analysis suggested that down-regulation of CEACAM1 expression may be an independent factor for poor prognosis in BLBC patients. GSEA and KEGG analysis revealed that CEACAM1 was negatively related with signaling pathways including extracellular matrix (ECM) receptor interaction, focal adhesion, and cell adhesion. The results of in vitro experiments indicated that CEACAM1 not only induced apoptosis of BLBC cells, but also inhibited the invasive and metastatic ability of cancer cells.Conclusions: CEACAM1 may contribute to improving the OS of BLBC patients due to its ability to inhibit the proliferation and metastasis of cancer cells. Therefore, CEACAM1 could be used as a potential prognostic biomarker and therapeutic target in BLBC.

Objective: To investigate the patterns of local failure and prognosis in patients with locally recurrent nasopharyngeal carcinoma (rNPC) after primary intensity-modulated radiotherapy (IMRT). Methods: The data of 298 patients with locally rNPC after IMRT were retrospectively analyzed. Magnetic resonance images of the initial and recurrent tumors were reviewed and, for patients with extra-nasopharyngeal local recurrence, the gross tumor volume of local recurrence was transferred to the original IMRT plan for dosimetry analysis. Significant prognostic factors for overall survival (OS) were selected by multivariate Cox regression analysis. Results: The commonest recurrence sites were the nasopharynx (93%, 277/298) and skull base (53.7%, 160/298). Of the 21 patients with extra-nasopharyngeal recurrence (19 cases valid), 12 had in-field failures, 4 had marginal failures, and 3 had out-field failures. The ethmoid sinus (57.1%, 4/7) and nasal cavity (28.6%, 2/7) were the most frequent sites of marginal and out-field failures. After median follow-up of 37 months, the 3-year and estimated 5-year OS rates were 57.3% and 41.7%, respectively. Multivariate analysis showed that age, recurrence interval, plasma Epstein-Barr virus (EBV) DNA level, and recurrent T stage were independent prognostic factors for OS. Conclusions: Local failure after IMRT occurs most commonly in the nasopharynx and skull base. In patients with extra-nasopharyngeal recurrence, in-field failure remains the main failure pattern, and marginal and out-field failures mainly occur in the ethmoid sinus and nasal cavity. Elder age, shorter recurrence interval, detectable plasma EBV DNA, and advanced recurrent T stage are negative predictors of OS in patients with rNPC.

Background: S100A8/S100A9 belong to the S100 calcium-binding protein family and play an essential role in the progression of chronic inflammation in diseases. It also regulates various biological processes such as tumor cell survival, apoptosis, and invasive metastasis. The extracellular form of S100A8/S100A9 functions by modulating cellular oxidative metabolism and facilitating inflammation-to-cancer progression. This modulation occurs through specific binding to receptors like RAGE and TLR4 and activation of signaling pathways including STAT3 and NF-κB. In tumor cells, S100A8 and S100A9 induce phenotypic changes by influencing calcium ion concentrations and other pathways. However, the precise function of high S100A8/S100A9 expression in colorectal cancer cells remains unclear.Methods: To explore the role of S100A8/S100A9 in colorectal cancer, we used immunohistochemistry and data from GEO and TCGA databases to analyze its expression in colorectal cancer cells, normal intestinal mucosa, and adjacent tissues. Functional models of high S100A8/S100A9 expression in colorectal cancer cells were established through transfection with overexpression plasmids. Protein microarrays, enzyme-linked immunosorbent assays (ELISAs), and real-time PCR were employed to assess the expression and secretion of 40 cytokines. MTT and Transwell invasion assays were conducted to evaluate changes in cell proliferation, invasion, and chemotaxis. Finally, tail vein and subcutaneous tumorigenesis assays assessed cell proliferation and migration in vivo.Results: We observed significantly higher expression of S100A8/S100A9 in colorectal cancer epithelial cells compared to normal intestinal mucosa and adjacent tissues. Overexpression of S100A8/S100A9 in mouse colon cancer cells CT26.WT led to differential increases in the secretion levels of various cytokines (CXCL5, CXCL11, GM-CSF, G-CSF, IL1a, IL1b, sTNF RI, and CCL3). Additionally, this overexpression activated signaling pathways such as STAT3, NF-κB, and ERK-MAPK. The synthesis and secretion of inflammatory factors could be inhibited by using NF-κB and ERK-MAPK pathway inhibitors. Moreover, S100A8 promotes the proliferation and invasion of colon cancer cells. Notably, the CXCR2 inhibitor (SB265610) effectively reversed the phenotypic changes induced by the CXCL5/CXCR2 biological axis.Conclusions: Our findings indicate that increased expression of S100A8 and S100A9 in colon cancer epithelial cells enhances the secretion of inflammatory factors by activating NF-κB, ERK-MAPK, and other signaling pathways. S100A8 facilitates colon cancer cell proliferation, invasion, and metastasis through the CXCL5/CXCR2 biological axis.

Despite advances in the treatment of breast cancer, the disease continues to exhibit high global morbidity and mortality. The importance of neutrophils in cancer development has been increasingly recognized. Neutrophil extracellular traps (NETs) are web-like structures released into the extracellular space by activated neutrophils, serving as a potential antimicrobial mechanism for capturing and eliminating microorganisms. The roles played by NETs in cancer development have been a subject of intense research in the last decade. In breast cancer, current evidence suggests that NETs are involved in various stages of cancer development, particularly during metastasis. In this review, we try to provide an updated overview of the roles played by NETs in breast cancer metastasis. These include: 1) facilitating systemic dissemination of cancer cells; 2) promoting cancer-associated inflammation; 3) facilitating cancer-associated thrombosis; 4) facilitating pre-metastatic niche formation; and 5) awakening dormant cancer cells. The translational implications of NETs in breast cancer treatment are also discussed. Understanding the relationship between NETs and breast cancer metastasis is expected to provide important insights for developing new therapeutic strategies for breast cancer patients.

We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.