Journal of Cellular and Molecular Medicine最新文献

Lipid metabolism reprogramming is one of the most prominent characteristics of cancer, but it is still unclear which regulatory pathways underlie this process in cancer cells. Circular RNAs (circRNAs) represent a novel category of non-coding RNAs with multifaceted regulatory functions. While the biological roles of circRNAs in cancer have been elucidated, there remains a dearth of knowledge regarding their involvement and regulatory mechanisms in lipid metabolism within the context of cancer. This article provides an overview of the regulatory roles and specific mechanisms of circRNAs in cancer lipid metabolism reprogramming. By elucidating these mechanisms, it enhances our comprehension of the metabolic rewiring driving tumour development and uncovers new avenues for targeted therapy.

Kruppel-like factors (KLFs) constitute a crucial family of transcription factors that are engaged in a variety of biological processes, such as erythropoiesis as well as liver development. A growing body of research underscores the increasing importance of the KLF family in the context of hepatocellular carcinoma (HCC). Despite this, the exact function of KLF1 within HCC remains unclear. Our study demonstrates a significant upregulation of KLF1 expression in tumour samples from HCC patients compared to normal liver tissue, with higher expression levels strongly correlating with poorer survival outcomes. Notably, in vitro experiments have shown that KLF1 enhances liver cancer cell proliferation by inhibiting ferroptosis, and this inhibition is negatively correlated with the transcription levels of fatty acid synthase 4 (ACSL4). These findings suggest that KLF1 may exert its oncogenic potential by repressing ferroptosis through the inhibition of ACSL4 transcription. Further mechanistic investigations reveal that KLF1 inhibits ACSL4 expression via transcriptional repression and suppresses ferroptosis through the ACSL4/LPCAT3 axis, ultimately promoting HCC tumour growth as well as its advancement. In conclusion, KLF1 is essential for onset as well as development in HCC through inhibiting ACSL4 transcription along with ferroptosis, thereby presenting novel therapeutic targets for HCC treatment.

Helicobacter pylori poses a significant risk for gastric cancer (GC) development. H. pylori exploits carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) on GC cells (GCCs) to colonise the gastric epithelium. CEACAM1, CEACAM5 and CEACAM6 are known to interact with H. pylori. We explored the role of H. pylori in altering CEACAM levels in GCCs and the paracrine effect of infected GCCs on neighbouring uninfected GCCs and macrophages. H. pylori significantly upregulated CEACAM6. Elevated CEACAM6 in GCCs promoted cell proliferation, cell migration and cell invasion. The effect was further enhanced after infection with H. pylori. Similarly, soluble factors released by CEACAM6-transfected GCCs promoted the tumorigenic potential of uninfected GCCs. Macrophages are crucial for GC development and progression. Therefore, it was intriguing to know how CEACAM6 could influence the polarisation of macrophages during H. pylori infection. To study this, we co-cultured macrophages with either the empty vector or CEACAM6-expressing GCCs and found that H. pylori infection increased the M2 polarisation of macrophages co-incubated with CEACAM6-expressing GCCs. In summary, CEACAM6 was found to promote GC aggressiveness and alter macrophage polarisation. This information could be harnessed to develop future therapeutics for targeting GC.

Cervical cancer ranks as the second most prevalent cancer among women worldwide, and the primary treatment for advanced cases involves cisplatin-based chemotherapy. However, the duration of cisplatin treatment is typically short, with a median survival rate of approximately 1 year. This highlights the urgent need to enhance our understanding of cisplatin's mechanism of action in cervical cancer treatment. Our findings demonstrate that p53 induces the nuclear translocation of IFI16, leading to activation of the NF-κB signalling pathway. This activation plays a crucial role in protecting cervical cancer cells against cisplatin-induced apoptosis. The activation of NF-κB is independent of STING, which is a downstream molecule of IFI16. STING signalling activation by cisplatin may not be associated with cisplatin-induced apoptosis. To further validate this tumour-promoting effect of IFI16 during cisplatin therapy, we established a subcutaneous implantation tumour model using mouse cervical cancer (U14) cells and conducted additional in vitro experiments. We examined the role and mechanism of IFI16 in cisplatin treatment of cervical cancer. The role of IFI16 in cervical cancer progression deserves further study. Targeted inhibition of IFI16 may be a new way to increase cisplatin sensitivity of cervical cancer cells.

Ischemia-reperfusion injury remains a major challenge in free flap surgery, contributing to oxidative stress, inflammation, and cell death that impair tissue viability and outcomes. Remote ischemic preconditioning (RIPC) has emerged as a potential protective strategy by modulating cellular stress responses, but its molecular mechanisms in free flaps remain incompletely understood. We prospectively enrolled 36 female patients undergoing autologous breast reconstruction with mainly deep inferior epigastric perforator (DIEP) free flaps, randomised into three groups: No RIPC, Early RIPC (24 h preconditioning), and Late RIPC (1 h preconditioning). Tissue samples were collected pre-ischemia and post-reperfusion for immunohistochemical and multiplex protein analyses. RIPC did not reduce oxidative stress markers, as 4-hydroxynonenal (4-HNE) levels were comparable across groups, while 3-nitrotyrosine levels paradoxically increased after RIPC. Early RIPC selectively modulated cell death pathways, with decreased expression of mitochondrial apoptotic marker caspase 9 and reduced necroptotic activation of mixed lineage kinase domain-like protein (MLKL) after reperfusion. Caspase 8 showed a transient modulation, suggesting effects on apoptosis-necroptosis crosstalk. Cyclophilin A levels were elevated after reperfusion in RIPC groups, indicating an adaptive stress response. These findings suggest that early RIPC exerts selective protection by modulating apoptosis and necroptosis, rather than broadly reducing oxidative stress. RIPC may represent a targeted strategy to improve free flap survival in reconstructive surgery.

Abdominal aortic aneurysm (AAA) is the most prevalent and lethal form of arterial aneurysm, frequently manifesting asymptomatically until a catastrophic rupture occurs. While various diagnostic imaging tools and several potential biomarkers have been explored for the purpose of early AAA screening, the usage of liquid biopsy such as extracellular vesicles (EVs)-carried protein for the early diagnosis of AAA is still being overlooked. In this study, we enrolled 18 AAA patients and nine healthy normal controls, including data from the National Drug Clinical Trial Organisation-Vascular Surgery (NDCTO) (in-house cohort) and the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital) (external cohort). We employed Olink's proximity extension assay (PEA) technology based on the plasma EV proteins and first comprehensively characterised the proteomics landscape in circulating EV underlying AAA disease development. A complex profile of differential EV proteins and EV protein-protein interactions network in AAA patients was identified. The differentially expressed EV proteins in AAA patients were found to be significantly associated with several enriched pathways, including the cellular response to cytokine stimuli, inflammatory response, and the regulation of the glucocorticoid receptor (GR) pathway. Moreover, five hub proteins were identified as being of particular significance: these were Interleukin-4, Interleukin-6, MCP-1, Neurturin, and Oncostatin-M. The Olink proteomics technique was utilised in order to identify these proteins. The significance of these proteins was further validated through Western blotting and enzyme-linked immunosorbent assay (ELISA) in the external cohort. The five EV proteins displayed reliable performance and robustness for distinguishing AAA from healthy people, revealing high accuracy with AUC values of 0.760, 0.840, 0.800, 0.840, and 0.900, respectively. The present study has revealed the plasma EV proteins landscape within AAA and further uncovered their potential roles in the pathogenesis of the disease. This presents a new direction for clinical diagnosis and management of AAA. Consequently, these five EV proteins have the potential to serve as useful biomarkers for the diagnosis and prediction of AAA. Further research is warranted to explore their potential as therapeutic targets.

Obesity increases the likelihood of metabolic diseases and can affect stem cell function negatively. Here, we aimed to elucidate the mechanisms involved in the loss of stem cell function induced by obesity by assessing levels of oxidative stress (OS) and endoplasmic reticulum stress (ERS) in bone marrow-derived mesenchymal stromal cells (BM-MSCs) from healthy donors with a body mass index (BMI) of 25-30 (obese) and BMI > 30 (morbid obese). We assessed base levels of OS and ERS, activation of cellular response mechanisms, and the effects of Melatonin (MT), which is known to decrease OS, and TUDCA, which is known to decrease ERS. Loss of BM-MSC differentiation was correlated with the degree of obesity and associated with upregulation of OS and ERS. Increased BMI was accompanied by elevated intracellular ROS and accelerated senescence of BM-MSCs. Although treatment with MT and TUDCA was able to decrease OS and ERS in BM-MSCs from obese donors, cellular stress in BM-MSCs from morbid obese donors was irreversible. Therefore, it is imperative to treat and prevent obesity before the negative effects on stem cells become permanent and irreversible. Early treatment of obesity may not only prevent metabolic diseases; it may also protect tissue resident stem cells.

Breast cancer (BRCA) is characterised by complex cellular heterogeneity and differentiation hierarchies, which play a crucial role in bone metastasis and therapeutic resistance. However, existing classification systems remain inadequate in capturing these complexities, limiting their effectiveness in guiding treatment strategies. To address this gap, we integrated single-cell RNA-seq profiles, spatial transcriptomes, along with 1097 bulk RNA-seq profiles of TCGA-BRCA cohort to dissect the molecular landscape of BRCA. By performing UMAP analysis, we identified nine tumour clusters and three spatially distinct spot types (immune, stromal and malignant spots) and further delineated 11 differentiation states from 2493 malignant spots. Through clustering, monocle 2 pseudo-time and prognostic analyses, we identified the prognostic BRCA cell fate-related genes, then constructed a novel BRCA stratification system (four subtypes) with differential prognosis, biological plausibility and clinical significance. Also, least absolute shrinkage and selection operator (LASSO) regression analysis was performed for the BRCA cell fate-related genes in constructing a prognostic model. The model has modest accuracy and accordance (AUC = 0.708), which could distinguish BRCA patients into high-risk or low groups. With correlation analysis, regulation networks were constructed for different subtypes based on the key cell fate-related genes, transcription factors, metastasis-related pathways, immune components and so on, to investigate the regulatory relationships between primary BRCA and BRCA bone metastasis. Afterwards, we identified the most significant inhibitors (puromycin, MS-275, megestrol, aesculetin) for bone metastatic BRCA, which might have potential translational significance. In all, we developed a novel molecular stratification system for BRCA based on the cell fate-related markers of malignant cells, which offered strong translational potential for diagnosis, prognosis and personalised therapeutic interventions.

Psoriasis (PS) is a chronic autoimmune skin disease that poses a serious threat to over 100 million patients worldwide. An increasing number of studies have indicated that keratinocytes (KCs) play an essential role in the inflammatory progression of PS. The present study found that tumour necrosis factor superfamily member 14 (TNFSF14) and its two receptors were up-regulated in IMQ-primed KCs and psoriatic skin sections. It also revealed that blocking TNFSF14 signalling (via gene knockout or injections) with its receptors' soluble fusion proteins lymphotoxin beta receptor (LTβR)-immunoglobulin G Fc domain (LTβR-IgGFc) and herpesvirus entry mediator-IgGFc (HVEM-IgGFc) significantly alleviated imiquimod (IMQ)-induced psoriatic skin inflammation by attenuating epidermal hyperplasia, decreasing cellular proliferation, keratinisation, apoptosis, and inflammatory response. Accordingly, direct stimulation with recombinant TNFSF14 markedly enhanced KC abnormalities as evidenced by aggravated cell proliferation and keratinisation, increased cellular apoptosis, and up-regulated inflammatory cytokine expression. Mechanistic studies demonstrated that TNFSF14 mediates KC abnormalities via the nuclear factor-kappa B (NF-κB)/TWIST1 pathway. Taken together, our study findings indicate that TNFSF14-HVEM/LTβR promotes KC dysfunction and IMQ-induced psoriatic skin inflammation via enhancing NF-κB/TWIST1 signalling and suggest that TNFSF14 is a promising therapeutic strategy for the clinical treatment of PS.

Long noncoding RNAs (lncRNAs) are involved in the regulation of triple-negative breast cancer (TNBC) senescence, while pro-carcinogenic lncRNAs resist senescence onset leading to the failure of therapy-induced senescence (TIS) strategy, urgently identifying the key senescence-related lncRNAs (SRlncRNAs). We mined seven SRlncRNAs (SOX9-AS1, LINC01152, AC005152.3, RP11-161 M6.2, RP5-968 J1.1, RP11-351 J23.1 and RP11-666A20.3) by bioinformatics, of which SOX9-AS1 was reported to be pro-carcinogenic. In vitro experiments revealed the highest expression of SOX9-AS1 in MDA-MD-231 cells. SOX9-AS1 knockdown inhibited cell growth (proliferation, cycle and apoptosis) and malignant phenotypes (migration and invasion), while SOX9-AS1 overexpression rescued these effects. Additionally, SOX9-AS1 knockdown facilitated tamoxifen-induced cellular senescence and the transcription of senescence-associated secretory phenotype (SASP) factors (IL-1α, IL-1β, IL-6 and IL-8) mechanistically by resisting senescence-induced Wnt signal (GSK-3β/β-catenin) activation. Immune infiltration analysis revealed that low SOX9-AS1 expression was accompanied by a high infiltration of naïve B cells, CD8⁺ T cells and γδ T cells. In conclusion, SOX9-AS1 resists TNBC senescence via regulating the Wnt signalling pathway and inhibits immune infiltration. Targeted inhibition of SOX9-AS1 enhances SASP and thus mobilises immune infiltration to adjunct TIS strategy.