Journal of Cancer最新文献

Objective: To demonstrate the efficacy of photodynamic therapy (PDT) using hematoporphyrin derivative (HPD) nanomedicine in combination with conventional chemotherapy based on gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) magnetic resonance imaging (MRI) for hepatocellular carcinoma (HCC) therapy. Methods: HPD nanomedicine was prepared, and the cytotoxicity of HPD nanomedicine at different concentrations on HCC cells and the half-maximal inhibitory concentration (IC₅₀) were analyzed. Sixty HCC patients who visited our hospital from 2021 to 2023 were retrospectively analyzed. Patient data were analyzed, with 30 cases in control group (CG) receiving conventional chemotherapy for HCC, and 30 cases in observation group (OG) receiving conventional chemotherapy combined with HPD nanomedicine PDT. Gd-DTPA MRI was utilized to monitor the morphological and biological characteristics of the lesions in patients. After treatment completion, the long-term efficacy of patients and the levels of bcl-2 and bax proteins in primary HCC cells were evaluated. Results: The IC₅₀ values of HPD on HepG2 cell proliferation and the cell inhibition rates gradually increased with increasing doses of HPD (50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.13 μM, 1.56 μM, 0.78 μM). HPD exhibited great anti-proliferative effects on HepG2 cells at relatively low concentrations. The differences in expression rates of bcl-2 protein and bax protein between groups were considerable (P<0.05). There were neglectable changes in AST and ALT levels between the two groups before treatment, but they were markedly reduced after treatment versus before treatment (P<0.05), with OG showing considerably lower levels than CG after treatment (P<0.05). Additionally, patients in OG exhibited better survival rates after the course of treatment versus those in CG. Conclusion: This study demonstrates that the combination of conventional chemotherapy based on Gd-DTPA MRI with HPD nanomedicine PDT greatly improves the efficacy of treatment for HCC patients. This combined treatment strategy not only enhances therapeutic outcomes but also alleviates adverse reactions associated with conventional treatment, providing a novel approach for future research in the treatment of HCC.

Purpose: Breast cancer poses a huge threat to the lives and health of women worldwide. However, drug resistance makes the treatment of breast cancer challenging. This study aims to investigate the effect of miR-141-3p on paclitaxel resistance and its underlying mechanisms in breast cancer. Methods: Using bioinformatics analysis and qRT-PCR to explore the potential molecule miR-141-3p. Specific binding of miR-141-3p to Keap1 was determined by using a dual luciferase reporter assay. qRT-PCR and Western blot were utilized to observe the expression of miR-141-3p, Keap1, Nrf2, SLC7A11 and GPX4. GSH/GSSG content, MDA content and JC-1 assays were used to observe the ferroptosis levels of breast cancer cells. CCK-8 assay was used to observe the cell viability of breast cancer cells. Tumor subcutaneous transplantation experiment was used to understand the effect of miR-141-3p on paclitaxel resistance in breast cancer in vivo. Results: In the present study, miR-141-3p was found to be highly expressed and associated with poor prognosis in breast cancer. miR-141-3p inhibited Keap1 expression, promoted Nrf2 expression, and facilitated paclitaxel resistance in breast cancer cells. Inhibition of miR-141-3p promoted Keap1 expression, inhibited Nrf2 and its downstream SLC7A11-GSH-GPX4 signaling pathway, as well as promoted ferroptosis in cancer cells, and inhibited paclitaxel and RSL3 resistance. ML385 blocks the effect of miR-141-3p on paclitaxel resistance and ferroptosis resistance in breast cancer cells. In vivo, miR-141-3p mimics promoted paclitaxel resistance, whereas miR-141-3p inhibitors inhibited paclitaxel resistance in breast cancer cells. Conclusion: This work revealed that modulation of the Keap1-Nrf2 signaling pathway by miR-141-3p promoted paclitaxel resistance via regulating ferroptosis in breast cancer cells.

Tumor-associated neutrophils (TANs) are increasingly recognized as contributors to cancer prognosis and therapeutics. However, TAN-related targets of breast cancer (BRCA) remain scarce. This study aimed to develop a novel TAN-associated risk signature (TANRS) of BRCA using single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. Eighty-six TAN-related genes (TANRGs) were derived from the intersection of TAN marker genes identified from scRNA-seq with modular genes identified by weighted gene co-expression network analysis (WGCNA). The TANRS consisting of nine TANRGs (TAGLN2, IGF2R, LAMP2, TBL1X, ASAP1, DENND5A, SNRK, BCL3, and CEBPD) was constructed using Cox regression and the least absolute shrinkage and selection operator (LASSO) regression. The TANRS efficiently predicted the survival prognosis and clinicopathological progression of patients across multiple cohorts. Significant differences in immune infiltration landscapes between TANRS groups were observed. Additionally, patients with high TANRS exhibited tumor immunosuppression, enhanced cancer hallmarks, and unfavorable therapeutic effects. Four promising compounds for treating high-TANRS BRCA were also presented. SNRK was identified as a key prognostic TANRG, and its expression profile and correlation with TANs were validated using immunohistochemical assays of BRCA samples and spatial transcriptomic sections. This novel TAN-based signature exhibited promising predictive capabilities, with the potential to contribute to personalized medicine for BRCA patients.

Background: Eosinophils, a type of white blood cell originating from the bone marrow, are widely believed to play a crucial role in inflammatory processes, including allergic reactions and parasitic infections. However, the relationship between eosinophils and liver cancer is not well understood. Methods: Tumor immune infiltration scores were calculated using single-sample Gene Set Enrichment Analysis (ssGSEA). Key modules and hub genes associated with eosinophils were screened using Weighted Gene Co-expression Network Analysis (WGCNA). Univariate and multivariate Cox analyses, along with LASSO regression, were used to identify prognostic genes and create a risk model. The Tumor Immune Dysfunction and Exclusion (TIDE) score was used to evaluate the immunotherapeutic significance of the eosinophil-associated gene risk score (ERS) model. Experiments such as flow cytometry, immunohistochemical analysis, real-time quantitative PCR (RT-qPCR), and Western blotting were used to determine gene expression levels and the status of eosinophil infiltration in tumors. Results: A risk trait model including 4 eosinophil-associated genes (RAMP3, G6PD, SSRP1, PLOD2) was developed by univariate Cox analysis and Lasso screening. Pathologic grading (p < 0.001) and model risk scores (p < 0.001) were found to be independent predictors of hepatocellular carcinoma (HCC) patient survival. Western blotting revealed higher levels of eosinophil peroxidase (EPX) in HCC tissues compared to adjacent normal tissues. Immunohistochemistry showed that eosinophils mainly infiltrated the connective tissue around HCC. The HCC samples showed low expression of RAMP3 and high expression of G6PD, SSRP1, and PLOD2, as detected by IHC and RT-qPCR analysis. The in vivo mouse experiments showed that IL-33 treatment induced the recruitment of eosinophils and reduced the number of intrahepatic tumor nodules. Conclusion: Overall, eosinophil infiltration in HCC is significantly correlated with patient survival. The risk assessment model based on eosinophil-related genes serves as a reliable clinical prognostic indicator and provides insights for precise treatment of HCC.

Actin, primarily a cytoplasmic cytoskeleton protein, is transported in and out of the nucleus with the help of actin-binding proteins (ABPs). Actin exists in two forms, i.e., monomeric globular (G-actin) and polymerized filamentous (F-actin). While G-actin promotes gene transcription by associating with RNA polymerases, F-actin can inhibit this effect in the nucleus. Unexpectedly, we found that lovastatin, an FDA-approved lipid-lowering drug, induces actin redistribution and its translocation into the nucleus in triple-negative breast cancer (TNBC) cancer stem cells. Lovastatin treatment also decreased levels of rRNAs and stemness markers, which are transcription products of RNA Pol I and Pol II, respectively. Bioinformatics analysis showed that actin genes were positively correlated with ABP genes involved in the translocation/polymerization and transcriptional regulation of nuclear actin in breast cancer. Similar correlations were found between actin genes and RNA Pol I genes and stemness-related genes. We propose a model to explain the roles of lovastatin in inducing nucleolar stress and inhibiting stemness in TNBC cancer stem cells. In our model, lovastatin induces translocation/accumulation of F-actin in the nucleus/nucleolus, which, in turn, induces nucleolar stress and stemness inhibition by suppressing the synthesis of rRNAs and decreasing the expression of stemness-related genes. Our model has opened up a new field of research on the roles of nuclear actin in cancer biology, offering potential therapeutic targets for the treatment of TNBC.

Objective: Investigating the interaction between Mast cells (MCs) and Mononuclear Phagocytes (MPs) in the tumor microenvironment (TME) of blader cancer (BCa) to uncover potential immunotherapeutic targets. Methods: Single-cell RNA sequencing (scRNA-Seq) was conducted on 12 BCa patients to identify distinct subgroups of MCs and MPs. Transcriptome data was analyzed to characterize the phenotype, gene enrichment, cell-cell communication, and biological processes. The expression levels of cytokines were assessed by enzyme-linked immunosorbent assay (ELISA), while the chemotactic effects of cytokines were evaluated through Transwell assay. Results: In muscle-invasive bladder cancer (MIBC), the proportion of interferon-stimulated MC subtype (Mast-ISG15) increased. Mast-IL13 subgroup and Mast-CCL2 subgroups were functionally enriched in interferon (IFN) and nuclear factor kappa-B (NF-κB) signaling pathways. The Mast-CCL2 subgroup overexpressed the CCL2 gene, which could chemoattract MPs through CCL2. In vitro experiments confirmed that under stimulation, activated MCs activated IFN and NF-κB signaling, increasing the secretion of CCL2 and IL-13, chemoattracted THP-1 monocyte. Conclusion: This study revealed the vital role of MCs in shaping the TME of BCa. And provides new insights for the precise treatment of BCa.

The occurrence and development of hepatocellular carcinoma (HCC) are closely related to abnormal apoptosis. Brf1 is highly expressed in HCC and has clinical prognostic value. Here, attenuation of Brf1-induced apoptosis was found, and the related mechanism was explored. In the study, general bioinformatics data for Brf1 were obtained from The Human Protein Atlas (HPA). Analyses of the clinical prognostic value of Brf1 in HCC were performed with the Xiantao Academic web server using R software. The basic data were obtained from the GTEx database and TCGA database. Brf1 conditional knockout mice were obtained by repeated mating of C57BL/6 Brf1LoxP/LoxP and C57BL/6 NS5A-alb-Cre-ERT2 mice and verified by genotyping. Liver function measurements, hematoxylin and eosin staining (HE), and immunohistochemistry (IHC) were performed to explore the cause of mouse death after Brf1 knockout. The Brf1 knockdown HCC cell model was generated using lentiviral vector-based shRNA transduction. Cell proliferation assays, plate colony formation assays, anchorage-independent colony formation assays and mouse subcutaneous tumor models were used to evaluate the progression of HCC. Western blot (WB) analysis, flow cytometry, and TUNEL assays were used to detect apoptosis. DNA sequencing, transcriptomics, and proteomics analyses were carried out to explore the antiapoptotic mechanism of Brf1. We found that Brf1 was highly expressed in HCC and had clinical prognostic value. Brf1 knockout led to liver failure and hepatocyte apoptosis in mice. Downregulation of Brf1 slowed HCC cell proliferation, colony growth, and mouse subcutaneous tumor growth and increased the sensitivity of HCC cells to apoptosis induced by chemotherapy drugs. The expression of Brf1 was positively related to that of the apoptosis gene Bcl-2. The sequencing, transcriptomics and proteomics analyses consistently showed that energy metabolism played an important role in Brf1 function, that protein-protein interaction was the primary mode, and that organelles such as mitochondria were the main sites. In Conclusions, downregulation of Brf1 inhibits HCC development by inducing apoptosis. Energy metabolism plays an important role in Brf1 function. These results provide a scientific basis for combating HCC.

The evidence from clinical studies suggests that lung carcinoma (LC) patients exhibit dysregulation in lipid metabolism. However, the causal relationship between plasma lipidome and LC, and whether inflammatory proteins mediate, remains to be determined. Genetic data for 179 plasma lipids and 91 inflammatory proteins were obtained from the latest published genome-wide association studies. Genetic data on LC and subtypes were from the largest available meta-analysis. The causal relationship between plasma lipidome and LC was determined by the two-sample Mendelian randomization (MR) method. Mediation MR analysis was employed to ascertain whether inflammatory proteins mediate the impact of plasma lipidome on LC. We identified 39 causal relationships between genetically predicted plasma lipidome and LC and subtypes. These relationships involve the influence of phosphatidylcholines, phosphatidylethanolamines, diacylglycerols, triacylglycerols, sphingomyelins, and Sterol esters. Additionally, the mediating role of 5 inflammatory proteins in the causal relationship between plasma lipidome and LC and subtypes was determined. Our results highlight the complex network of plasma lipidome and inflammatory proteins regulating LC. Integrating plasma lipidome and inflammatory proteins into clinical practice may open new avenues for the prevention and treatment of LC.

Lactate metabolism plays a vital role in tumor progression. Currently, gastric cancer (GC) has a poor prognosis. Therefore, our research aimed to investigate novel biomarkers related to lactate metabolism in patients. Patient data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were divided into subtypes based on the expression of lactate metabolism-related genes (LMRGs). Based on the subtypes, we identified coiled-coil domain containing 80 (CCDC80) for further investigation. Univariate and multivariate Cox regression models were constructed to determine the prognostic value of CCDC80 in GC. We further explored the mechanism by which CCDC80 affects GC prognosis using gene set enrichment analysis (GSEA). Immune infiltration and drug sensitivity analyses were also performed. Finally, immunohistochemical staining was used to evaluate CCDC80 expression in normal and tumor tissues. We observed that CCDC80 was overexpressed in GC samples and was significantly associated with T and pathological stages. Multivariate Cox analysis identified high CCDC80 expression as an independent prognostic marker. GSEA indicated that the oxidative phosphorylation pathway was highly enriched in the low CCDC80 expression group. Moreover, CCDC80 was associated with immune cell infiltration, especially that of M2 macrophages. Patients with higher CCDC80 expression exhibited lower sensitivity to paclitaxel. In conclusion, our findings demonstrate that CCDC80 is a critical regulator in GC progression and immune response and is associated with lactate metabolism, and it could be used as a novel biomarker for prognostic and chemotherapy treatment purposes.

LY6H, a member of the lymphocyte antigen-6(LY6) gene family, is located on human chromosomes 6, 8, 11 and 19. This superfamily is characterized by the presence of LU domains. It has demonstrated its emerging significance in various cancers including adenocarcinoma, bladder cancer, ovarian cancer and skin cancer. However, comprehensive pan-cancer analyses have not been conducted to investigate its role in diagnosis, prognosis and immunological prediction. By conducting comprehensive analysis of patient data obtained from publicly available databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), University of Alabama at Birmingham (UALCAN), The Comparative Toxicological Genomics Database (CTD), cBioportal, cancerSEA, and UCSC, we systematically investigated the differential expression of LY6H in 33 different types of human tumors. Additionally, we thoroughly analyzed the diagnostic, prognostic, and immunoinfiltration value of LY6H. Simultaneously, we examined the correlation between LY6H and tumor stemness, methylation patterns, drug sensitivity, gene alterations as well as single cell functions. Furthermore, protein-protein interaction networks and gene-gene interaction networks for LY6H were constructed. Moreover, we also explored the network relationship between LY6H and chemical compounds or genes. The results revealed that LY6H exhibited high expression levels in most cancers which were further validated through Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Immunohistochemistry (IHC) analysis using Hepatocellular carcinoma (HCC) samples. Moreover, LY6H displayed early diagnostic potential in 12 tumors while also showing positive or negative correlations with prognosis across different tumor types. Additionally, it was found that LY6H played a pivotal role in regulating immune-infiltrating cells across multiple cancers whereas the correlation between LY6H expression and immune-related genes varied depending on their specific types. Furthermore, the expression of LY6H was significantly associated with DNA methylation patterns in 21 cancers. Therefore, LY6H could serve as an adjunctive biomarker for early tumor detection as well as a prognostic indicator for diverse malignancies.