Translational Oncology最新文献

Tumor-associated mast cells in the tumor microenvironment play a critical and complex role in the progression of tumor malignancy. However, the key molecules that control mast cell activation and target the biological function of ovarian cancer (OC) cells are still not fully understood. In this study, we performed scRNA-seq on cells isolated from six cases of epithelial OC tissues (three cases of primary tumor and three of metastatic tumor), and we identified three mast cell subtypes, among which the proportion of the second group of mast cell subsets specifically expressing NR4A3 was significantly higher in the metastatic tissue than in the primary tissue, suggesting that NR4A3 expression of MC may be related to the metastasis and prognosis of OC. In vitro, the biological functions of constructed NR4A3^high bone-marrow-derived mast cells, such as degranulation response, showed a significant decline, but their secretion of high levels of CXCL16 and IL-8 promoted the polarization of macrophages to M2 through the STAT6 pathway, thus promoting the migration and invasion of OC. In ovarian tumor models in mice with mast cell deficiency (c-Kit W-sh/ W-sh), adoptive transfer of NR4A3^high mast cells can not only promote subcutaneous tumor growth, but also promote intraperitoneal tumor cell colonization, decrease the ratio of CD8+ T cells, and increase the ratio of M2 macrophages. These results indicate that NR4A3 can drive mast cells to release more CXCL16 and IL-8 and induce macrophage M2 polarization through STAT6 signaling pathway, thereby mediating the metastasis of ovarian cancer.

Oxaliplatin (OXA) is a common chemotherapeutic agent for advanced colorectal cancer. However, its effectiveness is limited by drug resistance, highlighting the need for combination therapies. In this study, Triptonide (TN), a diterpenoid compound is used to enhance the sensitivity of OXA, and the underlying mechanisms are investigated. Our findings indicated the combination of TN and OXA demonstrated strong synergistic anti-tumor effects across a broad concentration range in both HCT116 and LoVo cell lines, particularly at ratios ranging from 1:312 to 1:156. The combination of TN and OXA at low doses effectively inhibits growth and induces cell death in HCT116 and LoVo cells. TN and OXA cotreatment causes severe mitochondrial damage in colorectal cancer cells, leading to intracellular reactive oxygen species (ROS) accumulation, which subsequently triggers apoptosis and ferroptosis. Mechanistically, TN directly binds to BIM, a pro-apoptotic and ferroptotic protein, and stabilizes it. TN treatment led to increased expression of BIM and knockdown of BIM alleviated the growth inhibition of OXA in colorectal cancer cells. Finally, TN and OXA cotreatment significantly reduced the tumor weight and volume of LoVo-bearing nude mice in vivo. Taken together, our findings indicate that TN may serve as a novel therapeutic agent to enhance the efficacy OXA in the treatment of colorectal cancer.

Introduction: Irreversible acute kidney injury (AKI) caused by cisplatin limits its clinical use, and transient receptor potential anchor protein 1 (TRPA1) regulates cisplatin-induced nephrotoxicity (CIN) through NF-κB signaling pathway-mediated inflammation. Single nucleotide polymorphisms in TRPA1 and NF-κB1 genes may be associated with individual heterogeneous nephrotoxicity.

Materials and methods: In this paper, we investigated the association of 17 single nucleotide polymorphisms (SNP) of TRPA1 and NF-κB1 genes with cisplatin-induced acute nephrotoxicity. Nephrotoxicity and its severity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). SNPs were measured by 48-Plex SNPscan® high-throughput SNP typing echnology in DNA isolated from peripheral blood of 589 Chinese Han lung cancer patients (241 with CIN and 348 without CIN) treated with cisplatin regimen.

Results: TRAP1 gene rs920829 locus T allele carriers had a reduced risk of nephrotoxicity relative to C allele carriers (OR 0.684, 95 % CI 0.524-0.894, p = 0.003), and their additive and dominant models showed similar trends as well. However, the SNPs of NF-κB1 were not observed to be correlated with nephrotoxicity.

Conclusion: SNPs of TRPA1 have the potential as biomarkers for predicting cisplatin nephrotoxicity.

Mortality and treatment failure in cervical cancer (CC) patients are primarily due to extensive metastasis and chemoresistance. Immunotherapy has emerged as a crucial clinical treatment strategy for CC patients; however, the current methods and biomarkers are inadequate for accurately predicting immunotherapy responses and patient prognosis. This study comprehensively analyzed ferroptosis and cellular senescence, two processes intricately linked to tumorigenesis, progression, and therapy, utilizing multi-omics data from TCGA-CESC, GEO cohorts, and clinical data from CC patients. Based on ferroptosis- and cellular senescence -related patterns, two distinct clusters with divergent prognoses and tumor microenvironment (TME) characteristics were identified. A prognostic model was subsequntly constructed, demonstrating robust reliability in predicting CC prognosis and response to immunotherapy. Patients in the low-risk group exhibited enriched immune cell infiltration, lower TIDE scores, higher IPS scores, and higher expression levels of immune checkpoint inhibitor-related genes, such as PDCD1 and CTLA4, which were associated with improved overall outcomes. Validation with clinical samples confirmed the differential expression of model-associated genes in CC, further supporting the model's accuracy. This prognostic model provides valuable insights into predicting CC prognosis and optimizing immunotherapy, offering potential benefits for personalized treatment strategies.

Background: Glioma, particularly glioblastoma, is a highly aggressive brain tumor with poor prognosis and limited treatment options. Recent research highlights the role of MANF (Mesencephalic Astrocyte Derived Neurotrophic Factor) in tumor biology, yet its specific mechanisms in glioma remain underexplored. This study aims to elucidate the role of MANF in glioma and its underlying mechanisms of action.

Methods: We conducted bioinformatics analysis using TCGA data to identify MANF-related pathways, followed by cellular assays and subcutaneous tumor models for functional validation. Experiments included Western blot and qRT-PCR analysis to investigate the effects of MANF on glioma cell proliferation, migration, and stemness gene expression.

Results: MANF was found to be highly expressed in tumor tissues and associated with poor prognosis in glioma patients. Endogenous MANF regulates tumor cells by modulating the TGF-β/SMAD4/p38 pathway, promoting stemness and enhancing malignant behaviors, including migration and invasion. Exogenous MANF, however, did not significantly affect stemness gene expression but contributed to glioma cell proliferation.

Conclusions: MANF emerges as a promising therapeutic target for glioma. This study clarifies MANF's specific mechanisms, offering insights into its potential for targeted glioma therapies.

Purpose: TRIM6, an E3 ubiquitin ligase with tripartite motif, directly targets protein substrates for degradation through ubiquitination. Studies have shown that TRIM6 plays a significant role in tumor development in various human malignancies. Thus, the aim of this study was to investigate the importance of TRIM6 and its associated mechanism in promoting the progression of glioma.

Methods: The expression of TRIM6 and its prognostic value in glioma patients were collected from the TCGA and CGGA databases. The effects of TRIM6 on glioma were investigated in vitro by CCK8, colony formation, wound healing, and transwell assays. Co-IP and western blot analysis were used to detect the interaction between TRIM6 and FOXO3A. The effects of TRIM6 were verified in vivo in subcutaneously xenograft models, and tumor size, and immunohistochemical changes were observed.

Results: Our analysis of TRIM6 expression in glioma tissues revealed a high level of expression, and the heightened expression of TRIM6 showed a positive correlation with the unfavorable prognosis among glioma/GBM patients. Through loss-of-function and gain-of-function experiments, we observed a profound impact on the proliferation, invasion, and migration abilities of glioma cells both in vitro and in vivo upon deletion of TRIM6. Conversely, the overexpression of TRIM6 intensified the malignant characteristics of glioma. Additionally, our findings revealed a significant interaction between TRIM6 and FOXO3A, wherein TRIM6 contributed to the destabilization of FOXO3A protein by promoting its ubiquitination and subsequent degradation. Experiments conducted in the rescue study affirmed that the promotion of glioma cell proliferation, invasion, and migration is facilitated by TRIM6 through the suppression of FOXO3A protein levels.

Conclusions: These observations imply that the TRIM6-FOXO3A axis could potentially serve as an innovative focus for intervening in glioma.

Objective

Drug resistance greatly limits the therapeutic effect of a drug. This study aimed to explore the role of long noncoding RNA ZFAS1 in Donafenib resistance of hepatocellular carcinoma (HCC) cells.

Methods

The expression of CREB3, ZFAS1, and p65 in HCC cell lines was measured by RT-qPCR and western blotting. After transfection with sh-ZFAS1, sh-CREB3, or sh-CREB3 + oe-p65 in Donafenib-resistent (DR) HCC cell lines, the transfection efficiency was evaluated by RT-qPCR and western blotting. The proliferation and IC₅₀ to Donafenib of HCC cell lines was examined by MTT assay. Cell proliferation and apoptosis were examined by colony formation and flow cytometry assays. Then, the correlation amongst CREB3, ZFAS1, LSD1/CoREST, and p65 was analysed by ChIP, dual-luciferase reporter gene, and RIP assays.

Results

ZFAS1, CREB3, and p65 were upregulated in HepG2-DR and Huh7-DR cells. Silencing of ZFAS1 or CREB3 enhanced the sensitivity of HCC cells to Donafenib, inhibited cell proliferation and IC₅₀, and increased cell apoptosis, which were reversed by p65 overexpression. Mechanistically, CREB3 bound to ZFAS1 promoter to augment ZFAS1 transcriptional expression, and ZFAS1 recruited LSD1/CoREST to the p65 promoter region to decrease H3K4 methylation and elevate p65 transcriptional expression.

Conclusion

CREB3 overexpression contributed to Donafenib resistance in HCC cells by activating the ZFAS1/p65 axis.