JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

The competing endogenous RNA hypothesis offers new insights into tumour progression, yet its role in posttreatment nasopharyngeal carcinoma relapse remains unclear. This study constructed ceRNA networks to identify molecular markers associated with NPC relapse. Three pairs of primary and relapse NPC tissue samples, along with their matched adjacent tissues, were collected for the RNA and miRNA sequencing, screened and identified relapse-related specific differentially expressed genes. We identified relapse-specific differentially expressed genes and functional analyses revealed enrichment in translation, biosynthesis, metabolism, TCA cycle, cell cycle, p53 signalling and immune pathways. Then these relapse-associated differentially expressed mRNAs, lncRNAs, and miRNAs were utilised to construct regulatory networks, resulting in a ceRNA network comprising 813 mRNAs, 143 lncRNAs, and 24 miRNAs, along with a survival-associated subnetwork of 23 mRNAs. Key mRNAs, such as UBC, PLA2R1, PTPRO, SMC5, PFN2, TIMM17B, NT5E and PCSK5, were validated via qPCR in NPC cell lines and tissues. To our knowledge, this is the first study to construct a comprehensive ceRNA network specifically for posttreatment recurrent NPC. These findings highlight the ceRNA network as a valuable framework for elucidating the mechanisms of NPC relapse and for identifying potential biomarkers for prognosis and therapeutic targets in recurrent nasopharyngeal carcinoma.

This study aims to elucidate the correlation between the lactylation-related genes and the progression of knee osteoarthritis (KOA). Integrating genome-wide association study data and expression quantitative trait locus data, Mendelian randomisation (MR) and summary-data-based MR analyses assessed the correlation between lactylation-related genes and KOA, validated candidates in chondrocytes by RNA-seq, western blotting (WB) and quantitative reverse transcriptase PCR (qRT-PCR). Moreover, CCK-8, transwell migration and scratch assays were conducted to assess the proliferation/migration. Finally, mediation analysis was utilised to explore the downstream mechanisms. LDHA and LDHC expression was significantly downregulated in the KOA group, as confirmed by RNA-seq, WB and qRT-PCR analyses. Functional experiments also confirmed that the down-regulation of LDHA or LDHC expression could produce a chondrocyte proliferation and migration inhibitory effect similar to that of the OA group, while restoring the expression of these two genes could significantly reverse this phenotype. Furthermore, mediation analysis revealed that CD38 on IgD + CD24− B lymphocytes mediated the protective effect of these genes against KOA, with CD25+ memory B cells also serving as mediators for LDHC's impact on KOA. LDHA and LDHC are identified as therapeutic targets for KOA, providing promising targets and ideas for the development of new treatment strategies.

Considering the distinct etiological pathways and molecular characteristics of different lung cancer subtypes, it is crucial to develop subtype-specific prevention strategies and therapeutic targets. This study aimed to identify protein biomarkers and potential therapeutic targets for specific subtypes of lung cancer by integrating population-based observational studies and Mendelian randomisation (MR) analyses. The cohort study was conducted in the UK Biobank, including about 47,000 participants whose blood samples were measured for 2,923 unique proteins and who were followed for the development of lung cancer. Two-sample MR was performed leveraging publicly available data from genome-wide association studies (GWAS) and protein quantitative trait loci (pQTL). Proteins were prioritised based on consistent associations across logistic regression, MR, transcriptomic validation and sensitivity analyses. Tier 1 proteins passed all evaluations, including GP1BA (squamous cell carcinoma) and ACADSB (small cell carcinoma). Tier 2 proteins, supported by transcriptomic evidence but not sensitivity analyses, included AGRN, ITGB2, SEPTIN3 (adenocarcinoma) and DPP10 (squamous cell carcinoma). Tier 3 proteins, supported by logistic regression and MR only, included CD5L, GNPDA, ACAN, C7, DMP1, HEPH, CEACAM6, COX6B1, CPXM2 and IL12RB2. Druggability evaluation suggests that existing drugs targeting ITGB2, GP1BA, ACADSB and COX6B1 could potentially be repurposed for the treatment of specific lung cancer subtypes.

Prostate cancer (PCa) is the second most prevalent malignancy in men, and therapeutic options become severely limited once androgen deprivation therapy (ADT) fails. This study evaluated the antitumor activity of Annonacin, a natural acetogenin, alone or in combination with docetaxel (DTX) in PCa. The antitumor effects and underlying mechanisms of Annonacin and/or DTX were investigated in DU145 cells and a xenograft mouse model by assessing proliferation, migration, apoptosis, colony formation, DNA damage and FAK expression and distribution. Through an integrated strategy combining network pharmacology and a series of in vitro assays, the findings demonstrated that Annonacin exerts significant antitumor activity by inducing DNA damage and downregulating FAK expression and localisation. Co-treatment with DTX further enhanced these effects, with combination index (CI) values < 1, indicating strong synergism. In vivo, the combination therapy achieved more than 74% tumour growth inhibition (p < 0.0001), accompanied by increased tumour cell death, reduced Ki-67 expression and elevated γ-H2AX levels. Collectively, these findings demonstrate that Annonacin exerts potent antitumor activity and synergistically enhances DTX efficacy by promoting DNA damage and suppressing FAK signalling, supporting its potential as a promising adjuvant candidate for PCa treatment.

Lung cancer prognosis varies significantly among patients, highlighting the need for accurate prediction tools. Emerging evidence suggests that the immune microenvironment plays a crucial role in lung cancer progression and treatment response. We collected RNA expression profiles and clinical data of lung cancer patients from TCGA and GEO databases. Differential expression analysis identified 276 lung cancer-associated genes using strict statistical criteria (logFC > 1, FDR < 0.05). Unsupervised consensus clustering divided patients into ‘lung cancer-related’ and ‘non-lung cancer-related’ subgroups. We evaluated 10 machine learning algorithms and 101 algorithmic combinations for prognostic model development. Single-cell RNA sequencing data were analysed using Seurat and CellChat to investigate immune cell interactions within the lung cancer microenvironment. Our prognostic model demonstrated excellent predictive performance with AUC values of 0.874, 0.891 and 0.925 at 1, 2 and 3 years, respectively (C-index = 0.874). Six key immune genes (TLR2, TLR4, CCR7, IL18, TIRAP and FOXP3) showed cell-type specific expression patterns in the lung cancer microenvironment. Intercellular communication analysis revealed complex signalling networks between B cells, T cells, NK cells and dendritic cells. CIBERSORT and ESTIMATE analyses confirmed significant differences in immune infiltration between high-risk and low-risk patients, with distinct patterns of T cell subsets, macrophages and dendritic cells. This study provides a reliable prognostic tool for lung cancer and offers insights into the critical role of the immune microenvironment in lung cancer pathogenesis. Our findings may guide the development of personalised immunotherapy strategies for lung cancer patients.

Lidocaine is widely used for perioperative pain management, but repeated exposure may cause neurotoxicity, including neurological deficits. This study investigates mechanisms underlying cognitive decline induced by repeated lidocaine exposure. Eighteen-month-old mice received repeated clinically relevant lidocaine infusions over 3 days. Cognitive function was assessed by Morris water maze, Y-maze and open field tests. Hippocampal pathology was examined via TEM, Nissl staining, immunofluorescence for astrocyte polarisation and Aβ deposition, and western blot for tau, BDNF, TrkB, mTOR and autophagy proteins. The TrkB agonist 7,8-DHF was used to modulate BDNF/TrkB/mTOR signalling. Repeated lidocaine exposure impaired cognition and induced Alzheimer's-like hippocampal pathology, as evidenced by increased accumulation of Aβ and tau toxic proteins, along with neuronal death. It reduced BDNF expression, inhibited TrkB phosphorylation, and activated mTOR signalling, leading to autophagy inhibition and pathological protein accumulation. Lidocaine shifted astrocytes towards the neurotoxic A1 phenotype, decreasing neuroprotective A2 astrocytes and BDNF synthesis. TrkB agonist treatment restored signalling, enhanced autophagy and improved cognitive deficits and pathology. Repeated lidocaine exposure promotes A1 astrocyte increase and A2 decrease, inhibiting autophagy via the BDNF/TrkB/mTOR pathway, resulting in toxic protein deposition and Alzheimer's-like cognitive impairment.

Acute myeloid leukaemia (AML) with isolated trisomies (ITs) represents a distinct cytogenetic subgroup with heterogeneous clinical behaviour and incompletely defined molecular features. To explore its genomic and transcriptomic landscape, we performed next-generation sequencing (NGS) on 14 AML patients harbouring isolated trisomies of chromosomes 8, 9, 10, 13, 14, 21 and 22. RNA sequencing (RNA-Seq) was conducted on 15 samples, including 12 with IT and 3 cytogenetically normal AML cases (normal karyotype, NK-AML) serving as controls. Trisomy 8 was most frequent, followed by chromosomes 13, 14 and 21. Recurrent mutations were identified in epigenetic regulators (DNMT3A, IDH1/2, ASXL1, TET2). Transcriptomic profiling stratified cases into IT-8, IT-21 and IT-13+22 subgroups. Gene set enrichment analysis (GSEA) revealed shared downregulation of cell cycle-related pathways (e.g., G2M checkpoint) and subgroup-specific patterns: oxidative stress and unfolded protein response in IT-8; epithelial-mesenchymal transition and oxidative phosphorylation in IT-21; inflammatory signalling (IL-6/JAK/STAT, TNF-α/NF-κB) in IT-13+22. A core set of 60 differentially expressed genes (DEGs) was shared, with nine hub genes related to cell cycle (MCM4, CDC7, CDC25A, DHFR), proteostasis (HSPA5, DNAJC3, CALR, HSP90B1) and inflammation. Drug sensitivity profiling revealed subgroup-specific vulnerabilities: IT-8 to DNA damage checkpoint inhibitors, IT-21 to PLK/mTOR inhibitors and IT-13+22 to BRAF/EGFR-targeted agents. These findings highlight AML-IT heterogeneity and therapeutic potential.

Long non-coding RNAs (lncRNAs) play important roles in colorectal cancer (CRC) progression. However, the biological function and regulatory mechanism of small nucleolar RNA host gene 26 (SNHG26) in CRC remain largely unexplored. SNHG26 expression was analysed in CRC tissues and cell lines using quantitative real-time PCR (qRT-PCR). The biological functions of SNHG26 were investigated through loss- and gain-of-function approaches. Interaction between SNHG26 and CDKN2A was examined by RNA immunoprecipitation, RNA pull-down and RNA stability assays. The effects of the SNHG26-CDKN2A axis on Cu + ELES(copper plus elesclomol)-induced cuproptosis and CD8+ T cell-mediated anti-tumour immunity were evaluated through cell viability, apoptosis, co-culture cytotoxicity and migration assays. SNHG26 was significantly upregulated in CRC tissues and cell lines, with high expression showing trends toward poor prognosis. SNHG26 knockdown suppressed CRC cell proliferation and enhanced apoptosis. Additionally, it increased sensitivity to Cu + ELES-induced cuproptosis. Mechanistically, SNHG26 directly interacted with CDKN2A mRNA, promoting its degradation. CDKN2A, which exhibits context-dependent effects in CRC, was post-transcriptionally regulated by SNHG26. Rescue experiments demonstrated that CDKN2A knockdown partially reversed the oncogenic effects of SNHG26 overexpression, including enhanced proliferation, reduced apoptosis and increased resistance to cuproptosis. Furthermore, the SNHG26-CDKN2A axis modulated the tumour immune microenvironment by regulating CD8+ T cell cytotoxicity and chemokine expression, specifically downregulating CXCL9 and CXCL10, which are critical for T cell recruitment. Our findings reveal a novel regulatory axis whereby SNHG26 promotes CRC progression by destabilising CDKN2A mRNA, resulting in enhanced cell proliferation, cuproptosis and immune evasion. This study provides new insights into the molecular mechanisms underlying CRC development.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer with restricted therapeutic options and unfavourable survival outcomes. To identify novel prognostic biomarkers and therapeutic targets, we investigated the role of macrophage polarisation in HNSCC progression. Using integrative computational approaches, including biological network algorithms and molecular subtyping, we established a robust gene signature associated with M1/M2 macrophage balance, which exhibited significant prognostic value in HNSCC patients. Further analysis employing multi-model machine learning algorithms pinpointed ZBP1 as the pivotal gene, linking it to key clinical and immunological features, including disease progression, immune microenvironment remodelling, tumour mutational burden, and response to immune checkpoint inhibitors. Mechanistic studies confirmed ZBP1's tumour-suppressive function, demonstrating its ability to inhibit HNSCC cell proliferation and migration in vitro. Moreover, macrophage co-culture assays revealed that ZBP1 modulates immune regulation by restricting macrophage recruitment and altering polarisation dynamics. Collectively, our findings highlight ZBP1 as a promising prognostic biomarker and a potential immunotherapeutic target in HNSCC. This study not only enhances our understanding of macrophage-mediated tumour immunity but also provides mechanistic insights into how ZBP1 integrates tumour-intrinsic and immune-regulatory pathways to influence HNSCC progression. These discoveries may contribute to the development of more precise therapeutic strategies for this aggressive malignancy.

Asherman Syndrome (AS) is caused by injury to the endometrium leading to uterine scarring, decreased menstruation and infertility; it typically occurs after surgical curettage of the uterus. AS is treated surgically albeit with limited success. Administration of bone marrow-derived mesenchymal stem cells (MSCs) has recently been demonstrated to restore uterine function in AS; however, there is no data available on the role of the estrous cycle phase on outcomes. Here, we describe endometrial injury during estrus or diestrus, its differential effect on fertility, and its response after bone marrow MSC treatment to reverse the infertility in a murine model. Endometrial injury in the estrus phase did not affect fertility outcomes whereas injury in the diestrus phase resulted in infertility. Bone marrow (BM)-derived MSC treatment without injury in the estrus or diestrus phase did not affect the pregnancy outcomes. BM MSC treatment following endometrial injury in the diestrus phase restored fertility. Immunofluorescence analysis revealed that vimentin or cytokeratin-positive BM-derived cells in the uterus were extremely rare. BM MSC treatment after injury increased CD45⁺ cells, indicating a role for immunomodulation in endometrial repair. Finally, qRT-PCR showed that Ccl3, Il-1β and Mmp3 gene expression was significantly higher in the endometrium of the injury + BM MSC group than in other groups. In summary, injury to the endometrium during the diestrus phase results in infertility that can be restored by the treatment of BM MSCs. The therapeutic effect of BM MSCs on the endometrium appears to be mediated primarily by immunomodulation rather than BM MSC engraftment.