Cellular senescence (CS) plays a crucial role in various diseases, but its role in hepatocellular carcinoma (HCC) remains unclear. CS-related genes were clustered to identify subtypes. A risk score was constructed and validated in three independent cohorts. Associations with clinical characteristics, tumor immune microenvironment, mutation status, heterogeneity, and treatment efficacy were analyzed. Single-cell analysis was used to examine risk score distribution, and machine learning algorithms along with a nomogram were applied to assess prognostic value. Three CS subtypes were identified, with subtype 1 showing the worst prognosis. High risk score was associated with advanced clinical stage and grade, poor prognosis, and an immunosuppressive microenvironment driven by regulatory T cells. It also correlated with higher tumor mutations (notably TP53) and increased heterogeneity. High-risk patients showed poor response to sorafenib and transcatheter arterial chemoembolization (TACE) and may benefit less from immunotherapy. At single-cell level, the risk score was predominantly expressed in malignant hepatocytes and linked to cell stemness. The CS-related risk score is a potential prognostic indicator for poor outcomes in HCC, playing a significant role in tumor progression and offering potential value for clinical diagnosis and prediction of treatment response.
Shaoyang Lu, Junjie Ma, Xiao-Dan Wang et al.· Clinical and Experimental Me...· 0 citations
Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options, highlighting the urgent need to identify novel therapeutic targets. The present study investigates the role of the RNA methyltransferase METTL3 in promoting TNBC progression by modulating a ferroptosis-related phenotype, an iron-dependent form of regulated cell death. Using TNBC cell lines (BT549 and MDA-MB-231), we demonstrated that METTL3 overexpression significantly enhanced cell proliferation, while its knockdown suppressed growth. Mechanistically, METTL3 was associated with decreased lipid peroxidation, reactive oxygen species (ROS), intracellular Fe2 + levels, and the pro-ferroptotic protein ACSL4, alongside increased glutathione and the key ferroptosis inhibitor GPX4. Bioinformatic analysis, MeRIP-PCR, and actinomycin D chase assays indicated that METTL3 was associated with increased N6-methyladenosine (m6A) enrichment, expression, and persistence of ELF1 mRNA. Dual-luciferase reporter assay further suggested that ELF1 may be involved in GPX4 transcriptional regulation. Crucially, the pro-proliferative and ferroptosis-associated effects of METTL3 overexpression were partially attenuated upon ELF1 knockdown or treatment with the ferroptosis inducer erastin. In conclusion, our findings suggest a novel METTL3/ELF1/GPX4 axis through which METTL3 promotes TNBC growth by regulating oxidative stress and ferroptosis-related markers, providing a basis for further investigation of this pathway in the context of TNBC biology and therapeutic development.
Jin-Chen Wang, Wei Wang, Jun-Jie Hu et al.· Asia-Pacific Journal of Clin...· 0 citations
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