Cancer Cell International最新文献

Objective: To investigate the significance of DCUN1D5 in colorectal cancer (CRC) progression and determine the underlying mechanism.

Methods: We analyzed DCUN1D5 expression levels in CRC tissues using the TCGA and GEO databases and conducted immunohistochemistry and qPCR in retrieved CRC tissues. shRNA-mediated knockdown of DCUN1D5 in CRC cell lines was performed to investigate its effects on cell growth and motility. In addition, DCUN1D5-mediated promotion of CUL1 neddylation was examined using immunoblotting, the antitumor effects of inhibiting the neddylation pathway was evaluated using the inhibitor MLN4924, and the effects of silencing DCUN1D5 and MLN4924 treatment were validated in vivo using xenograft models.

Results: DCUN1D5 was found to be significantly overexpressed in CRC tissues, and its knockdown impaired CRC cell proliferation and migration, which was associated with reduced CUL1 neddylation. Inhibition of the neddylation pathway using the NEDD8 inhibitor MLN4924 supported these observations. In vivo, DCUN1D5 silencing and MLN4924 treatment led to reduced tumor growth and metastasis.

Conclusion: DCUN1D5 contributes to the growth and motility of CRC in vitro and in vivo.

Chemoresistance in esophageal cancer (EC) continues to impose formidable clinical challenges, driving disease recurrence and adverse outcomes. While vesicle-associated membrane protein 7 (VAMP7), a SNARE family regulator, has emerged as an oncogenic participant in tumor evolution, its mechanistic role in EC chemoresistance remains uncharted. Clinico-pathological analyses reveal pronounced VAMP7 overexpression in EC specimens, correlating with unfavorable prognosis, metastatic dissemination, advanced tumor staging, and cisplatin-refractory phenotypes. Functional interrogation demonstrates that VAMP7 silencing attenuates malignant hallmarks-proliferation, migratory capacity, and epithelial-mesenchymal transition (EMT)-while potentiating apoptotic cascades. Mechanistically, VAMP7 exhibits robust positive correlation with ferroptosis regulators GPX4 and NRF2, establishing its role as a ferroptosis checkpoint inhibitor that sustains cisplatin resistance. Combinatorial VAMP7 depletion and cisplatin treatment synergistically diminished neoplastic viability through dual mechanisms: amplification of ferroptosis biomarkers (lipid peroxidation, iron dysregulation) and induction of mitochondrial ultrastructural derangements. Conversely, ectopic VAMP7 expression in resistant clones upregulated GPX4/NRF2 axis activity and reinstated chemotolerance. Therapeutically, co-administration of ferroptosis agonists (RSL3/Erastin) with cisplatin abrogated VAMP7-mediated resistance, evidenced by suppressed xenograft growth and amplified mitochondrial pathology in preclinical models. This work identifies VAMP7 as a novel ferroptosis-chemoresistance nexus in EC, offering a translational framework for overcoming cisplatin refractoriness through coordinated inhibition of VAMP7 signaling and ferroptosis potentiation.

Breast cancer is one of the most prevalent malignant tumors among women worldwide. The incidence of breast cancer in China has been steadily increasing, posing a significant public health concern that gravely jeopardizes women's well-being. Given the heterogeneity and drug resistance associated with breast cancer, conventional treatment methods are inadequate to meet current therapeutic demands, necessitating the urgent development of new biomarkers and therapeutic targets. Ferroptosis, characterized by iron-dependent lipid peroxidation-induced cell membrane rupture, represents a form of programmed cell death. As ferroptosis gains increasing attention for its role in cancer biology, its potential value as an anti-cancer therapy is being gradually explored. However, our understanding of tumor cell ferroptosis in breast cancer remains incomplete, particularly at the single-cell level where knowledge is limited. Therefore, delving into the heterogeneous response of breast cancer cells to ferroptosis and elucidating its regulatory mechanisms hold great significance for comprehending the biological behavior of breast cancer and devising novel therapeutic strategies. In this study, we reanalyzed single-cell RNA-seq data from 26 breast cancer patients using a non-negative matrix (NMF) algorithm. GSEA enrichment analysis was employed to identify tumor subsets most susceptible to ferroptosis while pseudotiming was utilized to pinpoint MXRA8 as a key gene regulating ferroptosis. CellChat was applied to explore relationships between different subsets and various immune cell populations. Finally, we conducted in vitro experiments to validate MXRA8's involvement in regulating ferroptosis in cancer cells. This study unveils the crucial role played by ferroptosis-related tumor subsets in breast cancer progression and tumor immunity.

Biliary tract carcinoma (BTC) is an aggressive cancer with a poor prognosis, and chemotherapy's effectiveness is limited, especially after first-line therapy failure. Circulating tumor cells (CTCs) offer a promising platform for in vitro drug-sensitivity testing to optimize subsequent-line chemotherapy, but the clinical efficacy and prognostic value remain underexplored. In this study, we retrospectively analyzed 85 advanced BTC patients, with 25 receiving CTC-based drug-sensitivity-guided chemotherapy (CSBT), 15 receiving FOLFOX based chemotherapy, and 45 receiving empirical therapy. CTCs were enriched and tested for drug sensitivity using a glucose uptake assay. Therapeutic efficacy, including patient response, progression-free survival (PFS), overall survival (OS), and toxicity profiles, was evaluated. The results indicated that the objective response rate (ORR) was 16% in CSBT, 6.7% in FOLFOX, and 4.4% in the empirical group. The disease control rate (DCR) was significantly higher in CSBT group (56%) compared to the FOLFOX (20%) and empirical therapy (22.2%; p < 0.05) groups. Median PFS (mPFS) was significantly prolonged in the CSBT group (5.4 months) versus the FOLFOX (1.9 months) and empirical therapy (2.7 months; p < 0.05) groups. Median OS (mOS) was extended in the CSBT group (12 months) compared with the FOLFOX (5.1 months) and EBT group (7.8 months), with a significant improvement during the first year of treatment (p < 0.05). Toxicity profiles were similar across all groups. This study demonstrates, for the first time, that CTC-based drug sensitivity testing offers a potential strategy to guide subsequent anti-cancer therapy for advanced BTC, providing a safe and effective approach to improving patient prognosis.