Background Systemic lupus erythematosus (SLE) is characterized by chronic immune activation and molecular alterations that overlap with aging-related biological processes. However, how these alterations are organized across molecular layers and whether they converge on shared regulatory networks remain incompletely understood. Methods We performed an integrative multi-omics analysis combining in-house proteomic and phosphoproteomic data from 130 patients with SLE and 90 healthy controls (HCs) and publicly available transcriptomic datasets comprising 1,461 SLE patients. Proteins and phosphorylation sites were annotated using established aging-related gene resources. Differential protein abundance and phosphorylation changes were analyzed across disease-status and disease-activity comparisons. Nominal P-value thresholds were used for exploratory feature selection, whereas FDR-adjusted P values were used to assess robustness after multiple-testing correction. Kinase-substrate enrichment, transcription factor annotation, and cell-type-resolved transcriptomic comparison were used to explore potential regulatory programs. Results We identified 128 nominally altered proteins annotated to aging-related biological processes, including genomic instability, mitochondrial dysfunction, and epigenetic alterations. Phosphoproteomic analysis revealed 36 nominally altered phosphorylation sites, including previously unreported sites in IFI16 (S153, S780) and PKCδ (S507, S664). Clustering analysis demonstrated heterogeneous protein co-regulation patterns across disease states. Kinase activity inference suggested altered activity of TBK1 and IKKβ. TF analysis further highlighted STAT1, RELA, and PML as potential central nodes within the inferred regulatory network. Notably, these multi-omic alterations were not randomly distributed but showed convergence toward shared signaling pathways, particularly those related to interferon responses. Conclusions This integrative multi-omics study identifies inflammatory and interferon-dominated molecular alterations in SLE PBMCs that overlap with aging-related biological processes and converge on shared regulatory networks. These findings provide a hypothesis-generating framework for investigating the intersection between chronic immune activation and aging-related molecular remodeling in SLE.
Hong-Wei Zeng, Donge Tang, Yong Dai et al.· Frontiers in Immunology· 0 citations
Aim: Despite the contribution of cancer stem-like cells (CSLCs) to acquired paclitaxel resistance in non-small cell lung cancer (NSCLC), the biomarkers and regulatory mechanisms sustaining their stemness under chemotherapy pressure remain poorly understood. This study aimed to identify the stemness-maintaining programs underlying CSLC-associated paclitaxel resistance.
Methods: Paclitaxel-resistant NSCLC cell models were established. RNA-seq data from resistant spheres and adherent resistant cells were integrated with Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/gene set enrichment analysis and patient transcriptomic datasets to identify CSLC maintenance-associated candidate biomarkers. Inhibitors, sphere-forming assays, CD104-CD166+CD49fhi flow cytometry, reverse transcription quantitative polymerase chain reaction, western blotting, and ST6GAL1 knockdown or overexpression were used for functional and mechanistic validation. Sambucus nigra agglutinin lectin blotting was performed to assess epidermal growth factor receptor (EGFR) α2,6-sialylation. Clinical relevance was assessed using ST6GAL1 immunohistochemistry on 46 clinical lung tumor tissues.
Results: Paclitaxel-resistant NSCLC cells exhibited enhanced sphere formation and CD104-CD166+CD49fhi expansion. N-glycosylation was activated in resistant spheres. A seven-gene N-glycosylation signature was identified as a CSLC-associated candidate biomarker in acquired paclitaxel resistance. Inhibiting N-glycosylation suppressed the EGFR-mTOR-SOX2/BMI1 axis, decreased CSLCs, and restored paclitaxel sensitivity. ST6GAL1 regulated EGFR α2,6-sialylation. ST6GAL1 depletion also decreased EGFR abundance, suppressed mTOR-SOX2/BMI1 signaling, and sensitized paclitaxel-resistant spheres to paclitaxel rather than adherent cells. ST6GAL1 expression, which was higher in tumors from patients who underwent chemotherapy, showed a trend toward poorer survival among chemotherapy-treated patients. The seven-gene signature was associated with shorter disease-free survival but not overall survival in lung cancer patients.
Conclusions: ST6GAL1-mediated α2,6-sialylation of EGFR contributes to the maintenance of CSLC-associated paclitaxel resistance through mTOR-SOX2/BMI1 signaling. These findings identify ST6GAL1-dependent EGFR sialylation as a potential therapeutic target in CSLC-associated chemoresistance.
Yu-Xi Yang, Bing-Hui Liang, Wei-Jie Hong et al.· Cancer Drug Resistance· 0 citations
This study provides a systematic multi-omics characterization of immune microenvironment remodelling in CRC and identifies candidate molecular regulators that may serve as potential targets for future immunotherapy research.
Hong-Wei Zeng, Lie-Wen Lin, Yumei Chen et al.· Cancer Genomics & Proteomics· 0 citations
Epidermal growth factor receptor-targeted therapies such as afatinib provide clinical benefits to patients with advanced-stage non-small cell lung cancer (NSCLC); however, acquired resistance frequently develops, with the underlying mechanisms remaining undefined in 20–30% of cases. The present study established afatinib-resistant (AR) NSCLC cell lines and confirmed their resistance phenotype using Cell Counting Kit-8 (CCK-8) cell viability assays. Notably, these cells also exhibited cross-resistance to osimertinib. To elucidate the molecular basis of resistance acquisition, the time-resolved transcriptomic profiling of A549 cells was performed across three stages: Parental, afatinib-exposed (adaptive phase) and stable resistant cells. The analyzed results revealed the persistent upregulation of ABLIM3, HTR1D and HSPA1A, which was validated by reverse transcription-quantitative polymerase chain reaction. The meta-analysis of hazard ratios from The Cancer Genome Atlas demonstrated that the elevated expression level of the three-gene signature was significantly associated with tumor progression and an increased risk of disease recurrence. These transcriptional alterations were accompanied by the sustained activation of the MAPK/ERK signaling pathway, as evidenced by increased ERK1/2 phosphorylation detected using western blot analysis, which was positively associated with the expression level of the three-gene signature. Functional analyses further demonstrated that the pharmacological inhibition of MAPK/ERK signaling using selumetinib effectively re-sensitized AR cells to both afatinib and osimertinib, as demonstrated by restored drug sensitivity in CCK-8 assays. Collectively, these findings suggest that MAPK/ERK signaling contributes to the transition from adaptive tolerance to stable resistance to afatinib and highlight a tractable therapeutic vulnerability for overcoming resistance to tyrosine kinase inhibitors in NSCLC.
