Cancer gene therapy最新文献

B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy commonly found in pediatric patients. This study aims to screen hub genes in B-ALL and elucidate the role of peroxiredoxin 1 (PRDX1) in the modulation of ferroptosis. Bioinformatics analyses were conducted to identify pivotal genes in the GSE17703 and GSE48558 datasets. The biological effects of PRDX1 deletion in B-ALL cells and the xenograft tumor were evaluated using a series of functional assays. Ferroptosis was induced in B-ALL cells using erastin. Transcriptome sequencing was performed on Nalm-6 cells before and after PRDX1 knockdown. Forskolin was employed to explore the role of PRDX1 in the cyclic adenosine monophosphate (cAMP) pathway. Four pivotal genes were identified, with two genes upregulated and two downregulated. Depletion of PRDX1 suppressed the proliferative, migratory, and invasive abilities of B-ALL cells, whereas PRDX1 overexpression exerted the opposite effects. PRDX1 silencing promoted erastin-induced ferroptosis, including elevated levels of COX2, ACSL4, ferrous ions, ROS, and MDA, while reducing GPX4, GSH, and SOD levels. PRDX1 knockdown further reduced the viability of B-ALL cells treated with the ferroptosis activator ML210, and treatment with the ferroptosis inhibitor liproxstatin-1 significantly reversed the suppressive effect of PRDX1 knockdown on xenograft tumor growth. Mechanically, PRDX1 deletion triggered ferroptosis in B-ALL cells by inhibiting the cAMP pathway. PRDX1 deficiency modulates ferroptosis in B-ALL cells by blocking the cAMP pathway, which offer a novel perspective on the pathogenesis of B-ALL.

Mechanistic understanding of how transcription factors drive oncogene expression in lung cancer remains limited. Here, we utilized a cancer cell line-guided, multi-omic approach integrating promoter-capture Hi-C (pcHiC), ATAC-seq, ChIP-seq, and transcriptomics to identify epigenomic and 3D genomic alterations associated with oncogenes in non-small cell lung cancer (NSCLC) patients from The Cancer Genome Atlas (TCGA). Our cancer cell line accurately recapitulates key transcriptomic and epigenomic alterations observed in NSCLC patient samples. Comprehensive multi-omic analyses revealed aberrant activation of the bZIP family oncogenic transcription factor AP-1 in lung cancer cells. Clinically, AP-1 activation significantly correlated with patient outcomes in TCGA data, where elevated AP-1 expression levels were associated with increased mortality in lung squamous cell carcinoma patients. UMAP projections further demonstrated that AP-1-driven oncogene expression is specifically enriched in NSCLC patients exhibiting high AP-1 expression levels. Mechanistically, we observed enhanced promoter-enhancer interactions mediated by AP-1 at multiple upregulated oncogenes. Pharmacological inhibition of AP-1, either directly via AP-1 inhibitor SR11302 or indirectly through its upstream JNK pathway inhibition via SP600125, suppressed AP-1-driven oncogenic transcription and reduced promoter-enhancer looping. Our findings highlight the pivotal role of AP-1 in oncogenic transcription in NSCLC, revealing that transcription factors enhance oncogene expression by facilitating promoter-enhancer interactions.

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive kidney cancer with poor prognosis due to its frequent late-stage diagnosis and immunosuppressive tumor microenvironment (TME). While ccRCC is responsive to immunotherapies, treatment resistance remains a major challenge, underscoring the need for new therapeutic targets. We performed integrated single-cell and bulk transcriptomic analysis of ccRCC and normal kidney tissues to characterize the immune landscape and identify key ligand-receptor interactions within the TME. Gene expression and survival data were analyzed using public datasets. Functional validation was conducted using a ccRCC xenograft mouse model treated with the CSF1R inhibitor Sotuletinib. Single-cell analysis revealed that enhanced communication between M2-like macrophages and malignant epithelial cells in ccRCC, with the CSF1-CSF1R signaling axis playing a central role. Elevated expression of CSF1 and CSF1R correlated with poor patient prognosis and increased macrophage infiltration. In vivo inhibition of CSF1R reduced tumor growth, decreased Ki67+ cell proliferation, and suppressed CD163+ M2 macrophage polarization. This study suggests a potential role of CSF1-CSF1R-mediated macrophage-epithelial crosstalk in promoting immunosuppressive TME and tumor progression in ccRCC. Importantly, CellChat-based predictions represent potential, rather than definitive, ligand-receptor interactions, and thus require further mechanistic validation. Targeting CSF1R may offer a promising strategy to modulate the immune landscape and improve therapeutic outcomes in ccRCC.