International Journal of Biological Sciences最新文献

Recent studies have extensively addressed the potential role of the autonomic nervous system, which extensively innervates the pancreas, in the development of pancreatic ductal adenocarcinoma (PDAC). Targeting hypoxia-inducible factor-1 (HIF-1) for cancer management has attracted significant research interest, in view of the finding that HIF-1 regulates the expression of various genes involved in tumor angiogenesis, metastasis, proliferation, chemoresistance, and radioresistance. In this study, we investigated the molecular mechanisms by which the neurotransmitter acetylcholine enhances the expression of HIF-1α in pancreatic cancer cells in hypoxia. Under hypoxic conditions, acetylcholine induced a concentration-dependent increase in nAChR-α7-mediated HIF-1α expression in pancreatic cancer cells in vitro, leading to enhanced expression of HIF-1α target genes. It also increased HIF-1α protein stability in pancreatic cancer cells under hypoxic conditions. The acetylcholine-induced elevation of HIF-1α expression was blocked by siRNA-mediated knockdown of PDPK1/YAP signaling, indicating a role for this pathway in mediating these effects. A bioinformatics analysis of publicly available clinical datasets revealed that overall survival was significantly poorer in patients with CHRNA7 copy number amplification, whereas those with high CHRNA7 mRNA expression showed a non-significant trend toward reduced survival, suggesting that copy number alterations have stronger clinical relevance than mRNA levels. Functionally, α-bungarotoxin, a nAChR-α7-specific inhibitor, markedly blunted the acetylcholine-induced increase in the viability of pancreatic cancer organoids under hypoxic conditions. In a mouse xenograft model, acetylcholine administration accelerated tumor growth in animals bearing control pancreatic cancer cells but not in those implanted with nAChR-α7-knockdown cells. Collectively, our findings reveal a novel mechanism of acetylcholine-induced enhancement of HIF-1α expression involving PDPK1/YAP signaling and highlight the utility of HIF-1α as a therapeutic target in acetylcholine-potentiated pancreatic cancer.

Epigenetic mechanisms, including DNA methylation, frequently inactivate tumor suppressor genes (TSGs) in multiple tumorigeneses. This study investigated the molecular basis of the tumor-suppressive role of the classic protocadherin tumor suppressor PCDH10 in breast carcinogenesis. Frequent PCDH10 downregulation and promoter methylation was identified in breast cancer, correlating with poor prognosis and ER-negative status. Restoration of PCDH10 expression significantly suppressed tumorigenesis both in vitro and in vivo, by inhibiting epithelial-mesenchymal transition (EMT) and cancer stemness. RNA sequencing revealed PCDH10's role in Wnt/β-catenin signaling suppression. Mechanistically, PCDH10 enhanced GSK-3β phosphorylation at Try216, inhibited aberrant β-catenin activation and upregulated the expression of the tumor-suppressive nuclear envelope protein LMNA expression through direct binding. Concurrently, it also attenuated other oncogenic signaling via suppression of RhoA and Akt phosphorylation. Collectively, promoter CpG methylation-mediated silencing of PCDH10 promotes breast cancer progression. PCDH10 restoration antagonizes tumorigenesis by dual blockade of Wnt/β-catenin and Akt signaling pathways through interactions with GSK-3β, β-catenin, and LMNA, as a scaffold protein. Our findings reveal a novel PCDH10-dependent tumor-suppressive axis and highlight its potential as a therapeutic target and biomarker in breast cancer.

Purpose: DNA repair and DNA damage responses in cancer cells are regulated by metabolic reprogramming, which is increasingly recognized as a key factor contributing to PARP inhibitor (PARPi) treatment failure. This study aims to explore the metabolic mechanisms underlying PARPi resistance in PTEN-deficient prostate cancer and identify clinically viable metabolic interventions to overcome therapy failure. Experimental Design: A multicenter retrospective cohort was analyzed to evaluate the efficacy of combined metformin-PARPi therapy. Mechanistic studies utilized molecular assays to elucidate PARPi resistance and its critical determinants. Machine learning models predicting PARPi response were developed using clinical datasets and interpreted via SHAP analysis. Results: In PTEN-deficient cancer cells, lactate accumulation activated the NHE1/PKC/NOX1 axis, sustaining elevated NADP⁺ levels. NADP⁺ competitively inhibited the formation of PARPi-PARP-DNA complexes, leading to PARPi resistance. However, metformin administration significantly elevated NADP⁺ levels, inducing allosteric effects on PARP structures and enhancing PARPi efficacy. Based on these findings, we developed and validated a predictive machine learning model for PARPi response, which was interpreted using SHAP and deployed on a web platform. Conclusions: Metformin modulates NADP⁺ levels to influence PARPi sensitivity in PTEN-deficient prostate cancer. Additionally, we developed a machine learning model to provide clinicians with personalized predictions for PARPi response.

The dysregulation of ubiquitin-proteasome system (UPS) causes various diseases including cancer. The NF-κB signaling pathway, a critical regulator of inflammation and cell survival, is constitutively activated in pancreatic cancer (PC), but the role of UPS in its regulation is incompletely elucidated. Here, we found that E3 ubiquitin ligase FBXL8 is downregulated in PC tissues, and associated with poor patient prognosis. Functional experiments show that FBXL8 suppresses PC cells proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FBXL8 binds to dephosphorylated IκBα (S32/S36) and mediates K63-linked polyubiquitination at the K38 site of IκBα, thereby stabilizing IκBα and inhibiting NF-κB p65 nuclear translocation. Meanwhile, p65 upregulates the transcription factor YY1, which transcriptionally represses FBXL8 expression, thereby forming a FBXL8-NF-κB feedforward regulatory loop. In conclusion, this study reveals that FBXL8 suppresses PC progression by stabilizing IκBα through non-degradative ubiquitination, and its downregulation via the NF-κB-YY1 axis promotes oncogenic progression. The FBXL8-IκBα-NF-κB pathway represents a promising novel therapeutic target for PC.

Diabetic nephropathy (DN), a major complication of diabetes, is the leading cause of end-stage kidney disease; however, a comprehensive understanding of the dynamic immune-inflammatory changes during DN progression remains limited. We integrated single-cell RNA sequencing, in vivo diabetic models, and clinical samples from type 2 diabetes (T2D) patients to investigate cellular and molecular alterations across different stages of DN. Our results revealed a significant increase in immune cell infiltration in early DN in two mouse models. Notably, CCL4⁺ myeloid-derived suppressor cells (MDSCs) with a pro-inflammatory phenotype emerged as the predominant infiltrating immune population, with S100A9 highly expressed in these cells, serving as early molecular indicators. Compared to healthy individuals, T2D patients exhibited elevated levels of circulating MDSCs. Long non-coding RNA MALAT1 was identified as a key factor in maintaining MDSC function. In late DN, elevated expression of CD9 and TREM2 in kidney macrophages suggested a role for lipid-associated macrophages in DN progression. Concurrently, endothelial cell reprogramming characterized by GPX3 and SPP1 expression was observed during DN advancement. Furthermore, kynureninase, a key enzyme in the kynurenine pathway (KP), was upregulated in proximal tubule injury during early DN. The metabolites of KP including kynurenine, 3-hydroxykynurenine, and quinolinic acid were associated with enhanced induction of MDSCs in mice, as well as with adverse renal outcomes in T2D patients. Collectively, this study delineates the dynamic immune-inflammatory landscape of DN, uncovers key molecular players across disease stages, and provides novel insights into potential diagnostic markers and therapeutic targets.

Chronic stress is epidemiologically linked to metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying mechanisms remain unclear. In mice exposed to chronic restraint stress (CRS), we observed weight-independent hepatic steatosis with marked degeneration of sympathetic fibers. Stress elevated circulating norepinephrine levels but blunted hepatic β-adrenergic/cyclic adenosine monophosphate (cAMP) signaling accompanied by downregulation of β3-adrenergic receptor (β3-AR), indicating hepatic catecholamine resistance. Blocking hepatic sympathetic input prevented stress-aggravated steatosis and restored β-adrenergic signaling, whereas pharmacologic activation of β3-AR with mirabegron alleviated stress-induced lipid accumulation. Pseudorabies virus retrograde tracing and neuronal circuit interrogation further showed that projection from the medial central amygdaloid nucleus (CeM) to paraventricular hypothalamic corticotropin-releasing hormone (CRH^PVH) neurons mediated stress induced hepatic steatosis. Together, these results reveal a CeM-CRH^PVH-hepatic sympathetic axis that couples central stress signaling to peripheral β-adrenergic desensitization and lipid dysregulation, thereby suggesting a potential therapeutic strategy for stress-related MASLD.

The mortality of hepatocellular carcinoma (HCC) is high. Plant-derived bioactive compounds have emerged as potential therapies for HCC. Procyanidin (PAC) has been shown to possess immune-modulating and anti-tumor properties. However, the role and mechanism of total PAC in treating HCC remain unclear. We established subcutaneous and orthotopic HCC mouse models to assess the effect of PAC on tumor growth. Multi-omics analyses and in vitro experiments were conducted to investigate the changes in the gut microbiota, related-metabolites, and the tumor microenvironment (TME). 16S rDNA sequencing revealed that PAC could reshape the gut microbiota, notably increasing Lactobacillus murinus abundance. Furthermore, transplantation of Lactobacillus murinus reduced tumor volumes in mice. Single-cell RNA sequencing showed upregulation of the MAPK pathway in B cells within the TME. Metabolomic analysis suggests that 5-Hydroxytryptophan (5-HTP) derived from Lactobacillus murinus was significantly increased in B cells from mesenteric lymph nodes (MLNs) in the PAC-treated group. In vitro experiments revealed that 5-HTP could significantly upregulate the MAPK pathway in B cells. Additionally, 5-HTP-educated B cells could activate IFN-γ⁺CD8⁺T cells through B cell-T cell interactions, indicating that 5-HTP is a key metabolite in the therapeutic effect of PAC. Finally, feeding 5-HTP to HCC mice reduced tumor volume, upregulated the MAPK pathway in B cells from MLNs, and activated IFN-γ⁺CD8⁺T cells in the TME. PAC reshapes the gut microbiota and metabolites, upregulates the MAPK pathway in B cells from MLNs, and activates CD8⁺T cells in the TME through the gut-liver axis, thereby inhibiting HCC progression.

Nuclear and mitochondrial transcriptional regulation represent distinct mechanisms of gene expression control, both of which have garnered significant scientific attention. However, the interplay between these two regulatory processes remains poorly understood and underexplored. Our research uncovers a novel link between nuclear and mitochondrial transcription by identifying SIRT6 as an upstream regulator of the mitochondrial transcription factor TFAM, acting both indirectly and directly. Mechanistically, SIRT6 deacetylates FoxA1 at the K267 site, blocks the binding of FoxA1 to the promoter region of TFAM, leading to reduced TFAM expression. In parallel, SIRT6 translocates to the mitochondria and directly deacetylates TFAM at the K154 site, suppressing its transcriptional activity. Furthermore, SIRT6 downregulates the expression level of mitochondrial genes and proteins, inducing mitochondrial dysfunction and mitophagy by targeting TFAM. Additionally, TFAM promotes the growth and metastasis of colon cancer in vitro and in vivo, while SIRT6 was inhibited. In conclusion, our findings provide compelling evidence that SIRT6 establishes a network linking nuclear and mitochondrial transcription through the regulation of TFAM, identifying TFAM as a potential therapeutic target for cancer.

Trauma-induced Heterotopic ossification (tHO) is the abnormal osteogenesis occurring in soft tissues after traumatic musculoskeletal injury, which can lead to severe limb movement impairment or even disability. Recent studies have indicated that macrophages and mast cells play a crucial role in tHO, although their precise activation mechanism remained to be elusive. Here, we unveil a novel mechanism in which interleukin-33 (IL-33)-an alarmin in the mammalian innate immune response to trauma-rapidly increases upon tendon injury and binds to its receptor ST2 (IL-1RL1) on macrophages and mast cells. This binding initiates M2 polarization in macrophages and degranulation in mast cells, thereby promoting osteogenic differentiation during tHO formation. Mechanistically, the IL-33/ST2 axis leads to the autophagy defection in macrophages and mast cells. ST2-knockout (ST2-/-) markedly restores autophagy and mitigates tHO. Furthermore, we identified activation of the PI3K/AKT/mTOR pathway as a critical mechanism mediating IL-33-induced autophagy suppression. Restoration of autophagy via PI3K/AKT/mTOR pathway inhibitors similarly counteracts the aberrant osteogenic healing effects induced by IL-33. To explore a therapeutic strategy, we fabricated a bacterial cellulose (BC) hydrogel composite scaffold loaded with soluble ST2 (sST2), based on a competitive inhibition approach. These scaffolds successfully sequestered IL-33 during the early inflammatory phase, thereby alleviating macrophage- and mast cell-mediated inflammation and tHO formation. By identifying overexpression of the IL-33/ST2 axis in human HO tissues and further validating through animal experiments, this study elucidates how the alarmin IL-33 contributes to tHO via immune regulation. Our findings reinforce the pivotal role of autophagy in attenuating HO and provide new translational perspectives for its clinical treatment.

Aging-related bone loss is closely linked to mesenchymal stem cell (MSC) senescence, but the underlying epigenetic mechanisms remain unclear. Here, the role of histone H3 lysine 27 acetylation (H3K27ac) and its downstream target IGF2BP2 in MSC aging are investigated. Integrated ChIP-seq and RNA-seq analyses revealed diminished H3K27ac levels in aged murine bone marrow-MSCs (BM-MSCs), accompanied by reduced IGF2BP2 expression. Functional studies demonstrated that both knockdown and overexpression of IGF2BP2 mitigated senescence phenotypes in hydrogen peroxide- and etoposide-induced models. The mutation frequency of H65Q, a key point mutation in IGF2BP2, exhibited variations according to age and sex, and enhanced its binding to Hmga1 mRNA, stabilizing HMGA1 and activating the p53/p21 pathway to accelerate senescence. HMGA1 interacted with p53 to modulate DNA damage responses. Pharmacological inhibition of IGF2BP2 using CWI1-2 alleviated MSC senescence in vitro and enhanced bone regeneration in aged mice by improving bone mineral density and trabecular microstructure. These findings establish the H3K27ac-IGF2BP2-HMGA1 axis as a central regulator of bone aging and propose CWI1-2 as a promising therapeutic agent for age-related osteoporosis.