Cell Biochemistry and Function最新文献

This study aimed to investigate the prognostic significance and molecular mechanisms of antibody-dependent cell-mediated cytotoxicity-related genes (ADCC-RGs) in oral squamous cell carcinoma (OSCC). Transcriptomic data sets and clinicopathological characteristics of OSCC cohorts were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Subsequently, ADCC-RGs related to prognosis were screened. Prognostic ADCC-RGs were identified using Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) analyses and validated using Kaplan–Meier (K–M) survival and receiver operating characteristic (ROC) curves. Tumor immune cell infiltration analysis, chemotherapy drug analysis, gene set enrichment analysis (GSEA), and immunotherapy response prediction were conducted. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to assess the expression of model genes in clinical specimens, with parallel functional assays to evaluate the biological effects of key genes on OSCC cells. The novel nine-gene ADCC-RG risk stratification framework demonstrated robust predictive accuracy. The analysis indicated significant differences between the risk groups in terms of tumor immune invasion, chemotherapy drugs, GSEA, and immunotherapy response. Expression trends of the nine ADCC-RGs were verified in clinical samples. Low neuraminidase 1 (NEU1) expression inhibited CAL-27 and HSC-4 cell proliferation, migration, and invasion (all p < 0.05). In this study, a high-predictive-value prognostic model for OSCC was constructed based on nine ADCC-related genes; NEU1 was identified as a potential therapeutic target.

The tumor microenvironment (TME) is a complex ecosystem composed of cancer cells, stromal components, immune infiltrates, and neural elements. The presence and growth of nerves within or in close association with tumor tissue, a phenomenon known as tumor innervation, has long been observed. However, recent evidence supports a more active role for peripheral nerves in regulating cancer growth, metastasis, and therapeutic resistance. What remains underappreciated is the reciprocal influence of cancer cells on the nervous system. Accumulating data indicate that cancer cells remodel adjacent nerve terminals, triggering structural, neurochemical, bioelectrical, and transcriptional changes in a tumour-type-specific manner. These adaptations resemble pathways observed in nerve regeneration and suggest a tightly regulated, bidirectional signaling axis between cancer and nerves. In this review, we systematically consolidate emerging literature describing these nerve adaptations and categorize them across multiple levels, from morphological remodeling and neurotransmitter shifts to bioelectrical signaling and neuroimmune crosstalk. We highlight the central role of the tumor secretome in mediating nerve-cancer communication and emphasize how neural elements actively shape tumor behavior. By consolidating and critically examining findings across diverse cancer models and experimental systems, this review provides a mechanistic framework for understanding neural remodeling in cancer and identifies key areas for future investigation, including the potential of targeting nerve–tumor interactions as a therapeutic strategy.

Endoplasmic reticulum stress (ERS) has been implicated in the pathophysiology of intervertebral disc degeneration (IDD), yet the precise molecular mechanisms linking excessive ERS to pyroptotic cell death in nucleus pulposus cells (NPCs) remain elusive. This study aimed to elucidate how hyperactivated ERS promotes NPC pyroptosis and the subsequent release of inflammatory cytokines, focusing on the interaction between the PERK/eIF2α/ATF4 pathway and JAK1–STAT3 signaling. To investigate this, NPCs were subjected to tunicamycin (TM) to induce ERS, following which markers of pyroptosis (including NLRP3, Caspase-1, and GSDMD) and inflammatory cytokines (IL-18, IL-1β) were assessed. Additionally, small interfering RNAs (siRNAs) targeting components of the PERK/eIF2α/ATF4 and JAK1–STAT3 pathways were employed to delineate their roles. The results demonstrated that TM-induced ERS exacerbated pyroptosis and inflammation in NPCs, while silencing PERK or ATF4 significantly reduced pyroptosis, underscoring the importance of the PERK/eIF2α/ATF4 axis in this process. Notably, TM treatment also activated JAK1–STAT3 signaling, which was inhibited by PERK/ATF4 knockdown, suggesting a synergistic interaction between these pathways. Additionally, inhibition of JAK1 or STAT3 resulted in diminished pyroptotic activity and inflammatory cytokines release, highlighting the necessity of JAK1–STAT3 activation for ERS-driven pyroptosis. Mechanistically, PERK-dependent STAT3 phosphorylation was found to facilitate its nuclear translocation and subsequent transcriptional activation of genes associated with pyroptosis. In summary, this study demonstrates that ERS promotes NPC pyroptosis via PERK/eIF2α/ATF4-driven JAK1–STAT3 activation, identifying this pathway as a potential therapeutic target for disc degeneration.

Tumor invasion and metastasis, the leading causes of cancer-related mortality, are critically driven by cytoskeletal remodeling, a process extensively hijacked by oncoviruses to promote malignant progression. This review comprehensively examines how oncoviruses—including Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), and others—remodel key cytoskeletal components such as actin microfilaments, intermediate filaments (IFs), and microtubules (MTs). These virus-induced alterations facilitate epithelial-mesenchymal transition (EMT), enhance cell migration, and enable extracellular matrix degradation, thereby fostering tumor spread. We discuss specific mechanisms, including viral protein interactions and the deregulation of signaling pathways such as Rho GTPases and mTOR, which collectively orchestrate cytoskeletal dynamics to support invasion and metastasis. Furthermore, this review highlights emerging therapeutic opportunities, including targeting FSCN1 (Fascin Actin-bundling Protein 1, FSCN1) inhibition or using small-molecule inhibitors to disrupt oncovirus-mediated cytoskeletal changes and impede tumor progression. By bridging virology and cancer biology, this review provides novel insights for developing precision antimetastatic strategies and underscores the pivotal role of viral-cytoskeletal interplay in oncology.

Apolipoprotein A1 (APOA1), the main structural protein of high-density lipoprotein, has been implicated in cancer, but its role in lung adenocarcinoma (LUAD) remains unclear. Here, we integrate pan-cancer and LUAD-focused multi-omics with patient-serum validation, in-vitro and in-vivo functional assays, and drug-response/immune-infiltration analyses to define the role of APOA1. Public datasets (TCGA, HPA, UALCAN, cBioPortal) were used to profile expression, alterations, epigenetics, immune infiltration (CIBERSORT), and pathways (GO/KEGG/GSEA). Serum APOA1 was quantified in 60 LUAD and 30 healthy subjects. APOA1 was overexpressed in A549 and SPCA1 cells to assess proliferation, migration, and invasion; xenografts evaluated in-vivo growth. Drug-sensitivity correlations were analyzed. APOA1 is downregulated in LUAD and associates with worse survival; serum levels are reduced. Diagnostic performance was high (AUC = 0.942). APOA1 overexpression suppressed proliferation, migration, and invasion in vitro and reduced tumor volume in vivo. High APOA1 linked to complement/coagulation cascades and distinct immune infiltration. Drug sensitivity analysis revealed enhanced efficacy of agents like selumetinib in high-APOA1 tumors. This integrated, cross-layer evidence positions APOA1 as a tumor suppressor and actionable biomarker in LUAD, with implications for early detection, therapeutic stratification, and immunomodulatory strategies.

SENP3, a member of the sentrin-specific protease family, plays a pivotal role in lipid metabolism and the pathogenesis of fatty liver disease by regulating the dynamic process of SUMOylation. It has previously been demonstrated that SREBP2 is SUMOylated. However, the function and regulatory mechanism of SENP3-mediated SREBP2 de-SUMOylation in hepatocyte steatosis is unclear. Bioinformatic analysis (proteomes from whole cell extract and nuclear extraction, integrated transcriptomes, RNA sequence) SENP3-driven SREBP2 de-SUMOylation in lipid metabolism; Oil red O, nuclear and cytoplasmic extraction, western blot and immunofluorescence suggest SENP3 vitally contributes to hepatocyte steatosis; NLS predictions, CO-IP, co-transfection of plasmids, confocal microscopy indicates nuclear SENP3 associates with SREBP2 to promote its nuclear translocation; molecular docking and mutation assay confirmed SENP3 is responsible for de-SUMOylation SREBP2 at R576. Treatment with OA increased the level of both SENP3 and its nuclear fraction in HepG2 cells. Interfering with the SUMOylation and deSUMOylation cycle induced hepatocyte steatosis by overexpressing SENP3 and using a SUMO inhibitor, GA. Mechanistically, it is observed that the co-localization between SREBP2 and SENP3 is increased. SENP3 is responsible for de-SUMOylation SREBP2 at R576. Moreover, SENP3-mediated de-SUMOylation may also decrease ZMIZ1-ligated SUMO3 binding to SREBP2 at K464 in the nucleus. RNA interference of SREBP2 cannot reverse SENP3-overexpressed cell steatosis under fatty acid treatment. Expression of SREBP2 in vitro could upregulate the nuclear locations of CCTα binding to DNA without altering the active forms. Our findings demonstrate that de-SUMOylation is an important regulatory mechanism that governs the lipid accumulation of SREBP2 in mammalian cells. Also, the critical role of the de-SUMOylation of SREBP2 by SENP3 to exacerbate steatosis may be a potential therapeutic target for metabolic diseases like MAFLD/MASH.

Cancer immunotherapy, focusing on breaking tumor microenvironment (TME) immunosuppression, is limited by heterogeneity and drug resistance. Exosomes, 30–150 nm extracellular vesicles(EVs) carrying proteins, lipids, and noncoding RNAs, mediate intercellular communication and play dual roles in tumors. This review explores their multifaceted functions in cancer immunotherapy: in TME, tumor-derived exosomes (TDEs) drive immunosuppression, cancer-associated fibroblasts(CAFs) activation, and angiogenesis to promote progression and immune checkpoint inhibitors (ICIs) resistance; diagnostically, exosomal biomolecules (e.g., urinary miR-424/423/660/let-7i, serum LINC01125) serve as sensitive liquid biopsy markers for early detection and monitoring; therapeutically, engineered exosomes (e.g., DC-derived antigen-loaded ones) activate antitumor immunity and reverse ICIs resistance. These findings highlight exosomes' potential as diagnostic and therapeutic tools, laying a foundation for personalized cancer treatment.

Peptide drugs, with their unique properties of specific therapeutic effects and minimal side effects, are a promising avenue in cancer treatment. The MARCKS effector domain (ED) peptide has been found to inhibit MARCKS function or induce cell death. In this study, we investigated the cytotoxic efficacy of the non-phosphorylating MARCKS ED peptide with four serine (4S) of ED mutation to alanine (4 A) and with a transactivator of transcription (TAT) (termed 4A-TAT) fusion to improve cell permeating. We found that the 4A-TAT peptide caused acute and robust cytotoxicity against various tumor cell lines and had low toxicity to normal human B cells. Mechanistically, 4A-TAT rapidly disrupts plasma membrane integrity via pore formation, leading to calcium dyshomeostasis and organelle dysfunction, and ultimately inducing non-apoptotic cell death. In addition, the ED4A amino acid component is more critical than its order, and TAT is essential for the high sensitivity of cytotoxicity. Our study suggests that 4A-TAT peptide shows acute and robust killing effects on tumor cells in vitro and in vivo, making it a potentially intriguing cytotoxic peptide for tumor treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 32.4% of the global population. It is expected to be the primary cause of end-stage liver disease and liver transplantation. Obesity is a major risk factor for MASLD. However, a subset of patients with MASLD does not exhibit obesity-related traits, and this group is frequently neglected in clinical workups. Therefore, these patients do not receive timely diagnosis and treatment. Research has shown that MASLD is a multisystemic disease that is linked not only to type 2 diabetes mellitus but also to end-stage liver disorders (cirrhosis, liver failure, and hepatocellular carcinoma), cardiovascular disease, and chronic kidney disease. Thus, lean patients with MASLD are likely to develop liver fibrosis and end-stage liver disease. They are also at a high risk of cardiovascular disease and mortality. In this review, we systematically summarized the epidemiological characteristics and pathophysiological mechanisms of lean MASLD to elucidate the clinical profile and molecular basis of this disease subtype while proposing targeted integrated management strategies. By addressing critical gaps in current clinical practice, including shortcomings in screening, incomplete risk assessment frameworks, and the lack of individualized treatment approaches, this review provides practical guidance for reducing the risk of end-stage liver disease and extrahepatic complications in this patient population.