Cell Death & Disease最新文献

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal cell death in later stages. In this review, we aimed to critically discuss and highlight recent advances in the pathological footprints of amyloid-β and tau in AD. Specifically, we focused our attention on the interplay and synergistic effects of amyloid-β and tau in the pathogenesis of AD. We hope that our paper will provide new insights and perspectives on these pathological features of AD and spark new ideas and directions in AD research and treatment.

N4BP1 specifically degrades a subset of mRNA targets through their coding sequences and functions as a negative regulator of inflammation; however, its role in cancer development remains undefined. N4BP1 exhibits the highest expression in head and neck squamous cell carcinoma among all analyzed cancer types. Unlike wild-type mice, N4bp1^-/- mice did not develop visible tongue tumor masses in a 4-NQO-induced oral carcinogenesis model. Furthermore, N4bp1^-/- mice (86% vs 0%) exhibited significantly prolonged survival compared to wild-type mice within 26 weeks in 4-NQO-induced oral carcinogenesis model. Single-cell profiling demonstrated that N4BP1-deficient epithelial cells arrest at an early stage of cancerous transformation, while wild-type epithelial cells efficiently progress to an advanced stage of cancer. In established human cancer cell lines, N4BP1 also plays a crucial role in proliferation, migration, colony formation, and in vivo growth. Transcriptome profiling identified CCL2 and GM-CSF as downstream targets of N4BP1 in oral cancer. Apart from its intrinsic role in cancer cells, N4BP1-deficient cancer cells induce the differentiation of macrophages into the M1 phenotype. In N4BP1-deficient tissues, CCL2 and GM-CSF were significantly increased, accompanied by the accumulation of M1 macrophages and neutrophils. Our results demonstrate that N4BP1 is an essential gene in tongue cancer development. N4BP1 not only drives cancer cell evolution but also establishes an immune-suppressive microenvironment. N4BP1 is an endoribonuclease that specifically regulates a subset of mRNA targets (including CCL2 and GM-CSF) and plays an essential role in oral cancer.

Lung cancer is one of the most common cancers worldwide and the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and has a 5-year survival rate of ~19%. Since more than half of NSCLC patients present with metastatic disease at the time of diagnosis, early diagnosis is crucial for providing patients with the most effective treatment strategy. This study integrated transcriptome data between cancer and adjacent tissues from GEO and TCGA databases through bioinformatics analysis, and screened zinc finger CCCH-type containing 15 (ZC3H15) as a key differentially expressed gene in NSCLC. ZC3H15 expression levels were found to be significantly higher in NSCLC tissue than normal tissue and correlated with tumor size, TNM stage, lymph node metastasis and poor prognosis of patients. Overexpression of ZC3H15 promoted the proliferation, migration and invasion of NSCLC cells through activation of the AKT-mTOR signaling pathway. To elucidate the underlying molecular mechanism, we determined that ZC3H15 could bind to PTEN through its DFRP structural domain and recruited the E3 ligase TRIM56 to promote PTEN ubiquitination. In addition, overexpression of ZC3H15 increased the resistance of NSCLC cells to cisplatin. Therefore, ZC3H15 promotes the malignant phenotype of NSCLC through recruitment of TRIM56 to ubiquitinate PTEN, decreasing its expression and driving increased AKT-mTOR signaling pathway and cisplatin resistance. These findings provide a scientific basis for the development of targeted therapies against ZC3H15, which may lead to new therapeutic strategies for NSCLC patients.

Non-tuberculous mycobacteria (NTM) infections are difficult to cure completely with current treatments, and no specific drugs are available. However, recent reports have indicated that immune checkpoint inhibitors may effectively treat pulmonary NTM infections. In this study, we investigated the expression of immune checkpoint molecules in macrophages, the host cells of NTM, and assessed their impact on the microenvironment of infected lesions. Bulk-RNA sequencing and western blot analyses revealed that macrophages infected with Mycobacterium avium, an NTM species, exhibited a pro-inflammatory phenotype and increased PD-L1 expression. Additionally, immunostaining of an NTM-infected mouse model and human tissues showed that increased PD-L1 expression in macrophages was associated with decreased T cell infiltration and increased T cell exhaustion (upregulated PD-1 expression) within infected lesions. These findings suggest that NTM infections evade cellular immunity by enhancing PD-L1 expression in macrophages. Therefore, PD-L1 inhibition may be a promising therapeutic strategy against NTM infections.

X-ray repair cross-complementing protein 4 (XRCC4), a non-homologous end-joining protein involved in DNA double-strand break repair, is highly expressed in human cancer cells and tissues. A prior OGT interactome study identified XRCC4 as a candidate for O-GlcNAcylation. O-GlcNAcylation levels, a post-translational modification found on nuclear and cytosolic proteins, are also elevated in various cancers. However, the direct regulatory mechanism linking O-GlcNAcylation to XRCC4 function in cancer cells remains unclear. Here, we found that XRCC4 is O-GlcNAcylated at threonine 308, enhancing its stability by inhibiting TRIM21-mediated ubiquitin-dependent proteasomal degradation. O-GlcNAcylation elevated XRCC4 protein levels during DNA double-strand break damage, thereby conferring resistance to such damage. Additionally, XRCC4 Thr308 O-GlcNAcylation promotes cancer proliferation, invasion, and in vivo tumor growth. These findings suggest that downregulating O-GlcNAcylation on XRCC4 could be a potential therapeutic strategy to increase cancer sensitivity to chemotherapy or radiotherapy.

Angioimmunoblastic T-cell lymphoma (AITL) represents the second most prevalent subtype of peripheral T-cell lymphoma, characterized by a dismal prognosis. However, a systematic exploration of tumor microenvironment (TME) features and their prognostic significance in AITL remains notably deficient. To address this knowledge gap, we conducted spatial transcriptome sequencing (ST-SEQ) and whole-exome sequencing in four AITLs and two noncancerous lymph nodes for discovery purposes, complemented by immunohistochemistry analyses on 37 AITL cases for validation. We identified 14 ST clusters, including five neoplastic clusters, wherein a global shift in B-cell phenotypes and enrichment of myeloid cells were observed. These findings underscore a hallmark of exacerbated inflammation and immune dysregulation within the neoplastic TME. Among the 4 ST-sequenced AITLs, 3 expressed high CD40-CD40LG activity, accompanied by the upregulation of immune-suppressive-associated genes, such as CCL17 and PDCD1. Conversely, the remaining patient displayed an uncommon absence of CD40-CD40LG activity but harbored a phagocytosis-associated tumor-associated macrophage (TAM)-enriched TME, which correlated with significantly reduced relapse rates and longer event-free survival (EFS), highlighting the critical value of precise TME stratification in tailoring AITL therapeutic strategies. Finally, trajectory analysis unveiled a distinct trajectory of molecular evolution within this TME landscape. Collectively, our findings illuminate the heterogeneity and prognostic implications of the TME in AITL, providing a robust foundation for the rational design of targeted immunotherapeutic approaches. These insights may substantially advance the development of personalized treatment strategies for AITL patients.

Concurrent chemotherapy is the standard treatment strategy for advanced-stage nasopharyngeal carcinoma (NPC). However, chemoresistance inevitable develops and the underlying mechanism remains poorly understood. In this study, we identify the arginine methyltransferase PRMT5 as a key gene associated with chemoresistance to paclitaxel in NPC. We demonstrate that PRMT5 facilitated paclitaxel resistance by inducing KCNMB4 expression in nasopharyngeal carcinoma cells. Mechanistically, PRMT5 is recruited to the promoter region of KCNMB4, where it catalyzes H3R2me2s and enhances KCNMB4 expression. Furthermore, elevated levels of PRMT5 or KCNMB4 correlated with poorer survival and higher recurrence rates in NPC patients. Notably, genetic or pharmacological inhibition of PRMT5 significantly sensitized NPC cells to paclitaxel, both in vitro and in vivo. Collectively, these results suggest that the PRMT5-KCNMB4 axis plays a crucial role in mediating chemoresistance in NPC and targeting this axis may provide a promising therapeutic strategy for late-stage NPC patients.

The degeneration of the muscle in muscle dystrophies involves complex interactions among the different cell types. Here, we have used datasets from single-nuclei RNA sequencing (snRNAseq) of Duchenne Muscular Dystrophy (DMD) muscle samples to study the dysregulation of molecular pathways compared to healthy control muscle. We have observed that the epidermal growth factor (EGF) signaling is upregulated in DMD by an increase of the ligands EGF and EGF containing fibulin extracellular matrix protein 1 (EFEMP1). This study explores the role of EGF and EFEMP1 in FAPs and myoblasts in vitro. We provide evidence that EFEMP1 is secreted by FAPs in DMD and is mainly involved with increased myotube size but without enhancing muscle strength. Conversely, EGF enhances fibrotic differentiation in FAPs and promote smaller, proliferative myotubes in myoblasts, aligning with a fibrotic and dysfunctional muscle phenotype in DMD. The cellular differences from both ligands can be explained by the interactions with the receptor type, with EGF activating both EGFR and ErbB2, while EFEMP1 selectively maintained ErbB4 in an inactive state but promoting EGFR-ErbB2 and ErbB2-ErbB4 heterodimerization, potentially enhancing EGF signaling. Consequently, this study examinates the alteration of the EGF signalling in DMD and provides new molecular interactions in muscle that can be useful for targeted therapies of muscle degeneration.

Prognosis for pediatric sarcoma (pSC)-affected patients, especially those with relapsed/refractory disease, is dismal. The available treatment options are unsatisfactory, challenging researchers to address this unmet need. The investigational B7-H3 targeted ADC vobramitamab duocarmazine (vobra duo) showed clinical effectiveness towards several B7-H3-positive adult tumors and pre-clinical efficacy in pediatric neuroblastoma models. Cytotoxicity of vobra duo was evaluated in 2D and 3D models toward pSC cell lines expressing B7-H3, showing a dose-dependent cell viability reduction. Proliferation was assessed by time-lapse single-cell segmentation. Compared to controls, vobra duo resulted in a significant increase in the cell doubling time. AKT/mTOR master effectors of cell proliferation were investigated by phospho-specific western blot assays. A down-modulation of phospho-AKT/ -P70 S6K and -4E-BP1 protein expression was detected in both A204 (rhabdomyosarcoma) and U-2-OS (osteosarcoma) cells, the most treatment-sensitive and resistant cell lines, respectively, suggesting their involvement in vobra duo-mediated anti-proliferative effect. In response to treatment, all cell lines underwent apoptotic cell death. A significant increase in the executioner cleaved caspase-3 was detected, and a partial but significant reversion of apoptotic cell death was noted following pre-treatment with the pan-caspase inhibitor, Q-VD-OP-h. Vobra duo also triggered caspase-independent apoptotic events: i) increased AIF nuclear translocation, ii) increased mitochondrial superoxide production, and iii) the depolarization of mitochondrial membrane potential. In vivo, the effectiveness of vobra duo was assayed by single and repeated intravenous administration in the mouse rhabdomyosarcoma model. The single injection of 3 mg/Kg of vobra duo induced a significant tumor growth delay. Repeated vobra duo doses ameliorated this outcome, reverting rhabdomyosarcorma to rhabdomyoma tumor, by increasing Desmin and Myogenin/Myf-4 differentiation markers expression, and reducing both Ki-67 and CD133. In conclusion, the in vitro and in vivo anti-tumor effects towards pSC highlight the need to extend the investigation to patient-derived preclinical models, to pave the way for clinical translation.

Mesenchymal stromal cell (MSC) differentiation is critical for the development, maintenance, and repair of bone tissue. MSCs also play a key role in regulating self-renewal and differentiation of normal hematopoietic and leukemic stem cells. Our prior work has identified a key role of taurine produced by bone marrow osteolineage cells in supporting the growth of taurine transporter (TauT or Slc6a6) expressing leukemia cells. Here, we analyze multiple murine non-hematopoietic bone marrow single-cell RNA-sequencing datasets and discover that TauT expression is enriched in MSCs in vivo. Although taurine supplements have been shown to mitigate bone defects in aged mice, its role in regulating MSC populations that give rise to bone cells is poorly understood. Using TauT genetic loss-of-function murine models, we find that TauT loss impacts murine MSC populations in vivo and impairs MSC osteogenic differentiation in vitro. This is associated with decreased bone mineral density and bone strength in young and aged TauT knockout mice. Importantly, shRNA-based knockdown of TAUT expression in primary human donor MSCs reduces osteogenic differentiation. TauT null MSCs are unable to support self-renewal and expansion of co-cultured hematopoietic stem and progenitor populations, indicating broad functional defects. Mechanistically, TauT loss results in downregulation of inositol metabolism, increased oxidative stress, and reduced Wnt/β-catenin signaling, which induce MSC senescence. Collectively, our data identifies taurine as a key regulator of MSC maintenance and osteogenic fate determination.