Biochimica et biophysica acta. Molecular basis of disease最新文献

Psoriasis is a chronic skin disease occasionally associated with abdominal symptoms and IBD. We aimed to characterize intestinal immune cells and the integrity of the intestinal barrier in psoriasis. Biopsies from the duodenum and colon were analyzed by flow cytometry and immunohistochemistry for the presence and activation status of different immune cell populations. Intestinal permeability was measured using Ussing chambers. Proinflammatory markers were analyzed in fecal and blood samples using ELISA. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay. We found an increased density of intestinal eosinophils, mast cells, macrophages, and CD8⁺ T-cells in psoriasis; eosinophils, macrophages, and CD8+ T-cells expressed activation markers. Half of the psoriasis patients showed increased permeability across the duodenum, correlating with increased mucosal IL-17A, IL-13, IL-2, and IL-20, and with gastrointestinal symptoms. Our findings reveal that psoriasis is associated with low-grade intestinal inflammation, which may contribute to abdominal symptoms in these patients and possibly set the stage for the development of intestinal disease.

Background: Ubiquitin-specific protease 53 (USP53) deficiency is associated with familial intrahepatic cholestasis in which serum gamma-glutamyl transferase (GGT) activity is relatively low. However, how USP53 deficiency contributes to cholestasis is obscure. No animal model has been reported.

Methods: Usp53 liver-specific knockout (Usp53 cKO) mice generated by crossing Usp53^fl/fl mice with albumin-cre (Alb-cre) recombinase transgenic mice were challenged with dietary cholic acid (CA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). General well-being, hepatobiliary-injury biomarker values, histopathologic and ultrastructural appearances, and expression of key genes were compared with those in wild-type (WT) littermates. Interactions of USP53 and TJP2 were investigated by immunofluorescence and co-immunoprecipitation.

Results: Usp53 cKO mice exhibited no obvious differences from WT mice when fed with either normal-chow or CA-added diet. However, after 4 weeks of DDC feeding, Usp53 cKO mice lost less weight, were less icteric, had more nearly normal biomarker values, and accumulated less intrahepatic pigment than WT mice. On normal chow, mRNA expression of critical hepatic transporters Abcb11, Ntcp, and Abcc2 was lower in Usp53 cKO liver than in WT liver; after DDC feeding, mRNA expression of Tjp2 was higher, while detoxification enzymes Cyp3a11, Cyp2b10, and Sult2a1 was lower in Usp53 cKO liver than in WT liver, and hepatocellular tight junctions were significantly longer. USP53 interacts with TJP2.

Conclusions: Usp53 deficiency can protect mice from DDC-induced liver injury. Liver Usp53 cKO causes upregulation of hepatobiliary Tjp2, with biochemical and histologic features that largely mimic those of liver Tjp2 cKO, implying that USP53 deficiency may share similar mechanism to TJP2 deficiency.

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer representing approximately 25 % of all uterine malignancies. The molecular heterogeneity and pathogenesis of uLMS are not well understood, and translational studies aimed at discovering the vulnerabilities of this tumor type are of high priority. We conducted an innovative comprehensive multi-omics integration study from DNA to protein using freshly frozen tumors. Here, we show that two tumors harbor actionable therapeutic targets, IDH1_p.Arg132Cys and KRAS_p.Gly12Cys, and homologous recombination deficiency (HRD) is the most predominant genomic signature. Additionally, 80 % of the samples presented a chromothripsis signature, reinforcing the aneuploidy phenotype of these tumors. Tumors with a high proliferation score and high Ki67 expression was associated with worse overall survival (OS). We observed a high frequency of balanced fusion events involving EEF1A1 with enrichment of the EGFR pathway. For the first time, uLMS proteomics analysis showed the enrichment of pathways associated with suppression of the innate immune system and ECM organization. Finally, our comprehensive multi-omics integration analysis identified amplification of the CTHRC1 gene from the matrisome, with a negative impact on OS. Interestingly, the expression of Ki67 and CTHRC1 exhibits a strong negative correlation, underscoring two distinct and mutually exclusive biological profiles in uLMS: (i) highly proliferative tumors, characterized by elevated Ki67 expression, and (ii) tumors driven by ECM remodeling, marked by high CTHRC1 levels. Taken together, this deep functional multi-omics approach contributes to the detection of new molecular features of uLMS and suggests that patients could benefit from precision oncology in clinical practice.

Maintaining precise levels of FRG1 is vital. It's over-expression is tied to muscular dystrophy, while reduced levels are linked to tumorigenesis. Despite extensive efforts to characterize FRG1 expression and downstream molecular signaling, a comprehensive understanding of its regulation has remained elusive. This study focused on unravelling the cis -regulatory elements within the FRG1 gene and their interplay. Employing a dual luciferase reporter assay on fragments of the FRG1 promoter upstream of the transcription start site, we observed variations in FRG1 transcription induction. Our in-silico analysis unveiled binding sequences for Sp1 and DUX4 within FRG1 promoter region showing an enhanced luciferase signal. Conversely, we identified a YY1 binding sequence in the FRG1 promoter fragment showing decreased luciferase signal. Confirming these binding sites through site-directed mutagenesis, chromatin immunoprecipitation, and EMSA provided concrete evidence of Sp1, YY1, and DUX4's interaction within the FRG1 promoter. Additionally, interaction between Sp1, YY1, and DUX4 was elucidated using sequential chromatin immunoprecipitation (ChIP re-ChIP) and co-immunoprecipitation assays. Furthermore, alterations in the expression levels of Sp1, YY1, and DUX4 resulted in parallel changes in FRG1 gene expression. Notably, YY1 exhibited the ability to suppress SP1 or DUX4-mediated FRG1 transcription activation, while Sp1 and DUX4 together could counteract YY1-mediated transcription suppression. Our cell proliferation and colony formation assay underscored the tumorigenic properties of these three transcription factors through the modulation of FRG1 expression levels. The in vitro results were verified in vivo using mouse xenograft model. Leveraging RNA sequencing data from various tissues in the GTEx portal, we established a correlation between FRG1, Sp1, and YY1. In essence, this study revealed the vital cis-regulatory components residing in the FRG1 promoter. The combined influence of Sp1, YY1, and DUX4 plays a central role in controlling FRG1 expression.

Disturbances in lipid metabolism are closely related to intervertebral disc degeneration (IDD). However, the lipid metabolism characteristics of nucleus pulposus (NP) cells during IDD are unclear. Exercise protects against IDD and acts as a potent mediator of organ metabolism, in which muscle-secreted myokines actively participate. However, whether exercise-induced myokines alleviate IDD by regulating lipid metabolism in NP cells remains unknown. The present study revealed that lipid accumulation is the metabolic reprogramming phenotype in NP cells during IDD, which was attributed to an imbalance between increased fatty acid/triglyceride synthesis and diminished utilization, and was further associated with extracellular matrix (ECM) degradation and cell senescence. To explore the interaction between exercise and IDD, Sprague-Dawley rats were subjected to five weeks of treadmill running exercise, and rats in the exercise group exhibited less severe IDD than did those in the sedentary group. The expression of meteorin-like protein (Metrnl), a newly-discovered myokine that participates in lipid metabolism regulation, was observed to increase in muscle, serum and NP tissue after exercise. Moreover, Metrnl ameliorated lipid accumulation in NP cells and further alleviated ECM degradation and cell senescence. Mechanistically, Metrnl activated the fatty acid β-oxidation rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) via peroxisome proliferator-activated receptor α (PPARα) to increase lipid utilization in NP cells. This study provides insight into the lipid metabolic features of NP cells in IDD and reveals the intrinsic connections among exercise, metabolism and IDD, with the myokine Metrnl emerging as a pivotal mediator with therapeutic potential.

Ovarian cancer is the most common type of gynecological malignant tumor, with the highest mortality rate among female genital malignant tumors. In this study, we initially identified forkhead box F1 (FOXF1) as a potential prognostic biomarker of ovarian cancer through bioinformatics analysis. FOXF1 expression was higher in ovarian cancer tissue samples and served as an unfavorable prognostic factor. In vitro and in vivo experiments demonstrated that FOXF1 enhanced ovarian cancer cell migration and tumor dissemination. Chromatin immunoprecipitation-polymerase chain reaction and luciferase assays revealed that FOXF1 bound directly to the high-mobility group AT-hook 2 (HMGA2) promoter and significantly induced its transcriptional activity. Subsequent co-immunoprecipitation and mass spectrometry analyses demonstrated that HMGA2 stabilized S100 calcium-binding protein A6 (S100A6) protein through recruitment of the deubiquitinase, ubiquitin-specific peptidase 30 (USP30), thereby inhibiting S100A6 degradation. Rescue experiments further illustrated that FOXF1 induced ovarian cancer cell mobility in an HMGA2/S100A6-dependent manner. Additionally, FOXF1, HMGA2, USP30, and S100A6 were clinically relevant in patients with ovarian cancer. This is the first study to reveal the molecular mechanisms underlying FOXF1-mediated ovarian cancer metastasis and demonstrate that FOXF1 represents a potential therapeutic target in patients with metastatic ovarian cancer.

Background: Oxaliplatin is a commonly used platinum-based chemotherapy drug for patients with pancreatic cancer (PC). Drug resistance is a major challenge in PC treatment, underscoring the urgent need for new approaches. Targeting DNA damage repair, one of the factors responsible for platinum resistance, is an attractive strategy to overcome drug resistance. This study aimed to investigate the potential of the ATR inhibitor BAY 1895344 in improving the drug responsiveness of oxaliplatin-resistant PC.

Methods: Oxaliplatin-resistant PC cells (CFPAC-1 and Capan-2) were selected and treated with oxaliplatin, BAY 1895344, or a combination of both in vivo and in vitro. Their combinatorial effects on the DNA damage response (DDR) signaling pathway, apoptosis, and extent of DNA damage were evaluated using appropriate methods. Patient response was predicted using organoid models.

Results: Combination treatment with BAY 1895344 and oxaliplatin exhibited a synergistic effect on both PC cell lines, with the effect being more pronounced on Capan-2. Additionally, the combination treatment substantially suppressed phospho-Chk1, a coordinator of DDR and cell cycle checkpoints. Mechanistically, ATR inhibition augmented the DNA damage induced by oxaliplatin, leading to mitotic catastrophe and cell death. Furthermore, in an in vivo study using a tumor-bearing xenograft mouse model, the combination treatment markedly reduced tumor growth. This synergistic effect was confirmed in patient-derived organoids with poor response to oxaliplatin.

Conclusion: ATR inhibition enhanced the anticancer effect of oxaliplatin, suggesting that this combination treatment could be an effective therapeutic strategy for overcoming platinum resistance in PC.

Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.

Currently, the molecular mechanisms underlying bladder cancer progression remain unclear. Immune checkpoint inhibitors (ICIs) have been used to treat bladder cancer, but their efficacy is limited. Exosomes, which play a critical role in cell communication, can alter the tumor microenvironment. Therefore, it is essential to investigate the impact of bladder cancer exosomes on the tumor microenvironment. Our research demonstrates a significant up-regulation of miR-184 in exosomes derived from bladder cancer cells. miR-184 promotes bladder cancer cell proliferation in vitro and facilitates tumor growth in mice by targeting the 3' UTR of AKR1C3 mRNA. Additionally, miR-184 targets IRF2 mRNA, reducing its transcriptional inhibition on CXCL10. This process induces the expression of CXCL10, which promotes the infiltration of CD8+ T cells into the tumor. However, these infiltrating T cells become exhausted. In summary, our study reveals that bladder cancer-derived exosomes deliver miR-184, which targets AKR1C3, contributing to bladder carcinogenesis and development. We also investigate how the IRF2-CXCL10 pathway induces T cell exhaustion and leads to immune escape. This research provides new insights into the immunotherapy of bladder cancer, highlighting potential molecular targets for more effective treatment strategies.