Cell Death & Disease最新文献

Integration of high-risk human papillomavirus into specific loci of the genome is a pivotal event in cervical carcinogenesis; however, it's underlying mechanism remains largely undefined. Here, through establishing an 8q24 site-specific HPV18 gene knock-in cell model by utilizing the CRISPR/Cas9 system, we discover that HPV18 knock-in (HPV-KI) results in a global alteration of the genome's topologically associating domain structure and an up-regulation of cancer-related genes in HPV^- HaCaT cells, among which the significantly up-regulated IL-17 signaling pathway and S100A8/A9 are partitularly prominent. Further mechanistic study demonstrate that HPV-KI reprograms metabolic pathway, especially up-regulates glycolysis and subsequently facilitates glycerolipid synthesis in HaCaT cell, leading to sphingosine-1-phospate (S1P) secretion and enhanced SpHK1/S1P/S1PR1 signaling pathway, thereby activating the the MAPK and NF-κB signaling pathways followed by inducing the expression of S100A8/A9, and hence induces the malignant transformation of cells. Importantly, inhibition of the S1P/S1PR1 signaling pathway down-regulates the expression of S100A8/A9 and suppresses the growth of HPV-KI cells and xenograft derived from cervical cancer patient. These findings provide novel insights into HPV integration-induced cervical carcinogenesis and identify potential therapeutic targets for its treatment.

The impaired repair of intestinal mucosal damage is an important pathological feature of ulcerative colitis (UC). The critical role of intestinal epithelial cells (IECs) proliferation and migration in the repair of damaged mucosal epithelium has been well established. However, the molecular circuitry that decodes IECs sense intestinal mucosal damage signals to initiate and drive repair program remains elusive. Here, we identify a tryptophan (Trp) metabolic gatekeeping mechanism wherein G protein-coupled receptor 35 (GPR35) senses intestinal mucosal damage through monitoring Trp-kynurenine (KYN)-kynurenic acid (KA) axis metabolism with a unique "sandwich" structural binding mode. We delineate a GPR35-Kruppel-like factor 5 (KLF5) regulatory circuit in which KLF5 serves as the central effector, translating GPR35-mediated KA sensing into repair programming through PI3K-AKT-mTOR signaling cascade. This circuitry precisely orchestrates IECs proliferation and migration by regulating KLF5-dependent gene expression networks that essential for restoring damaged mucosa. Once this metabolic gatekeeping system is disrupted, either through impaired GPR35-mediated KA sensing or defective signal transduction, compromises damage signal decoding, leading to inadequate repair responses. Such dysregulation results in delayed intestinal mucosal repair and exacerbation of tissue damage. Our findings highlight GPR35 as a surveillant of abnormal Trp-KYN-KA axis metabolism, enabling IECs to detect intestinal mucosal damage and orchestrate repair through KLF5 response. This provides important implications for UC prevention and treatment by targeting GPR35-KLF5 circuit.

Metabolic reprogramming disrupts energy homeostasis and promotes tumor cell proliferation. In the present study, high expression of adipose triglyceride lipase (ATGL) in patients with acute myeloid leukemia (AML) predicted a poor clinical prognosis. Furthermore, the aberrant upregulation of ATGL was confirmed to promote the malignant progression of AML through gene ablation, overexpression, and pharmacological inhibition of ATGL, particularly in FLT3-ITD-mutated AML. RNA sequencing, lipid peroxidation, cellular iron, and ROS assays were performed to confirm the association of ATGL with ferroptosis. Mechanistically, ATGL is positively correlated with stearoyl-CoA decarboxylase 1 (SCD1) and promotes the malignant progression of AML by inhibiting ferroptosis through the CEBPα/SCD1 axis. We established gilteritinib-resistant MOLM-13 and MV4-11 cell lines and collected cells from patients with FLT3-ITD mutations to confirm that ATGL inhibitors increased the efficacy of gilteritinib. Consequently, we constructed an AML xenograft model using cells derived from patients with FLT3-ITD-mutated AML to confirm the efficacy of combining ATGL inhibitors with gilteritinib in vivo. This study provides novel therapeutic targets and monitoring indicators for AML, along with new treatment strategies for patients with FLT3-ITD-mutated AML and those with relapsed/refractory FLT3-ITD-mutated AML.

The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor owing to the lack of effective targeted therapeutic strategies. Thus, the exploration of the molecular pathogenesis of ICC is urgently required. The cytoskeleton protein, anillin (ANLN), has been reported to contribute to various tumor growth by participating in cytokinesis via RhoA signaling. However, the exact physiological role and potential regulatory mechanism of ANLN in ICC are still not well understood. Based on spindle-related genes, integrated bioinformatic analyses identified ANLN as a potential candidate target for ICC. ANLN was elevated in ICC and predicted worse survival. Mechanistically, VIRMA-mediated m6A modification and IGF2BP3-dependent interaction collectively accounted for the upregulation of ANLN by maintaining its mRNA stability. Furthermore, the combination of ANLN and VIRMA or IGF2BP3 offered a greater predictive value than each marker alone in a large ICC cohort. Functional studies indicated that ANLN was involved in cancer cell proliferation and cell cycle. ANLN knockdown induced cytokinesis failure, DNA damage, and apoptosis in ICC cells. In addition to discovering the crucial role of ANLN in cytokinesis via RhoA activation, we also illustrated that ANLN restrained the Hippo pathway by enhancing the activity of RhoA signaling, which together contributed to ANLN-mediated tumor-promoting effects on ICC. Furthermore, YAP1-TEAD1 transcriptionally activated ANLN, subsequently establishing a self-reinforcing loop between ANLN and Hippo pathway, which was mediated by RhoA signaling as an intermediate regulatory node. Importantly, two clinical drugs, the RhoA inhibitor simvastatin and the YAP1/TEAD inhibitor verteporfin were determined to be the disruptors of this feed-forward signaling axis, inhibiting ICC tumor growth. These findings reveal the vital function of ANLN in ICC growth and provide promising treatment strategies for ICC.

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.