Jul 2026· Journal of biochemical and molecular toxicology· Vol 40· 0 citations· 25 references
Medicine
TL;DR
It is revealed that the LINC02038/miR‐506‐3p/ATP7A axis played a crucial oncogenic role in HCC by driving tumor progression and modulating cuproptosis, and represents a promising prognostic biomarker and a potential therapeutic target for HCC intervention.
Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options, underscoring the urgent need for novel therapeutic targets. The copper transporter ATP7A has been implicated in cancer, but its precise role and regulatory mechanisms in HCC pathogenesis remain poorly understood. ATP7A expression was analyzed using public databases and validated in clinical HCC tissues and cell lines via qPCR and western blot. Functional assays were performed following ATP7A knockdown. Sensitivity to cuproptosis was assessed by measuring intracellular copper/ROS levels and IC50 of elesclomol‐Cu. The upstream regulatory axis was identified through bioinformatic prediction and verified by dual‐luciferase reporter and rescue experiments. The role of the LINC02038/miR‐506‐3p/ATP7A axis was further confirmed both in vitro and in a xenograft mouse model. ATP7A was significantly upregulated in HCC tissues and cell lines. ATP7A knockdown markedly inhibited HCC cell proliferation, migration, and invasion, while simultaneously sensitizing cells to cuproptosis. Mechanistically, LINC02038, which was highly expressed in HCC, functioned as a competing endogenous RNA (ceRNA) to sponge tumor‐suppressive miR‐506‐3p, thereby upregulating ATP7A expression. This LINC02038/miR‐506‐3p/ATP7A axis was demonstrated to coordinately regulate malignant phenotypes and the expression of key cuproptosis‐related proteins (DLAT, FDX1, LIPT1). In vivo, silencing LINC02038 effectively suppressed tumor growth and recapitulated the molecular alterations of this axis and cuproptosis regulators. Our findings reveal that the LINC02038/miR‐506‐3p/ATP7A axis played a crucial oncogenic role in HCC by driving tumor progression and modulating cuproptosis. This axis represents a promising prognostic biomarker and a potential therapeutic target for HCC intervention.
It is suggested that the LINC01446/miR-338-3p/APEX1 axis may contribute to ESCC progression and ferroptosis defense, warranting further investigation into its potential therapeutic and prognostic value.
Nasopharyngeal cancer (NPC) is a malignant tumor that originates from mucosal epithelial cells of the nasopharynx. As an emerging cancer‐associated microRNA, miR‐138‐5p has been shown to modulate various malignant cell malignancies. However, its precise biological function and regulatory mechanism in NPC remain to be further elucidated. Human NPC cell lines (HK‐1 and C666‐1) were used for in vitro study, and nude mouse xenograft models were used for in vivo investigations. A bioinformatic method was utilized for the prediction of RNA expression patterns and molecular interactions. RT‐qPCR was performed for the detection of miR‐138‐5p and CENPN expression. Luciferase activity detection and RNA pulldown experiments were used for verification of gene interaction. Flow cytometry and colony formation assays were conducted to evaluate cell cycle distribution, proliferative capacity, and apoptosis rate. Furthermore, extracellular acidification rate, lactate generation, and glucose uptake were assessed to explore the regulatory effects of miR‐138‐5p and CENPN on glycolysis in NPC cells. Protein levels of CENPN and key molecules associated with cell cycle, apoptosis, glycolysis, and the PI3K signaling pathway were quantified by western blot analysis. CENPN expression is analyzed to be upregulated in head and neck cancer samples, and its high expression is associated with unfavorable clinical prognosis. In NPC cells, miR‐138‐5p was markedly downregulated and was verified to directly target the 3′ untranslated region of CENPN, thereby negatively regulating its expression. Functionally, overexpressing miR‐138‐5p obstructed malignant phenotype, glycolysis, and tumor growth of NPC cells, where these inhibitory effects were significantly counteracted by enforced CENPN expression. Moreover, miR‐138‐5p overexpression inactivated the PI3K/Akt/mTOR signaling by reducing CENPN expression in NPC cells. In conlusion, miR‐138‐5p inhibits cell growth, glycolysis, and tumorigenesis in NPC by directly targeting CENPN, thereby inhibiting the PI3K/Akt/mTOR signaling pathway. These findings highlight the potential utility of miR‐138‐5p as both a diagnostic indicator and a therapeutic intervention target for NPC management.
Hong-Xia Guan, Yang Jiang, Hui Li· Journal of biochemical and m...· 0 citations
HCC (Hepatocellular carcinoma) is one of the malignant tumors with high morbidity and mortality worldwide. Its pathogenesis is complex and the efficacy of existing treatments is limited. Therefore, in-depth exploration of key regulatory molecules and their mechanisms is of great significance for the early diagnosis and targeted therapy of HCC. In this study, HCC cell lines Huh-7 and HepG2 were used as research models to systematically investigate the biological function and molecular regulatory mechanism of FAM117B (family with sequence similarity 117 member B) in HCC progression through gene knockdown and overexpression, cell functional assays, co-immunoprecipitation coupled with mass spectrometry, post-translational modification detection, transcriptome sequencing and nude mouse subcutaneous tumorigenesis assays. High FAM117B expression predicted poor prognosis and positively correlated with pathological grade; functionally, FAM117B exhibited robust oncogenic activity, where its knockdown suppressed proliferation, clonogenicity, invasion, and migration, and its overexpression enhanced these phenotypes. Mechanistic studies revealed that FAM117B directly physically interacted with NAT10 (N-acetyltransferase 10), an acetyltransferase, forming a bidirectional regulatory loop: on the one hand, FAM117B maintained the protein stability of NAT10 by inhibiting its K48-linked ubiquitination and subsequent proteasomal degradation; on the other hand, NAT10, as a key acetyltransferase, specifically mediated the acetylation of FAM117B at lysine 429, providing a molecular basis for the functional role of FAM117B. Transcriptome sequencing and molecular verification demonstrated that the FAM117B/NAT10 axis targeted and regulated JAK2 (Janus kinase 2) expression, activated the downstream JAK-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and thereby drove the malignant biological behaviors of HCC cells. In vivo, dual knockdown of FAM117B and NAT10 significantly reduced xenograft growth, decreased Ki67, and increased apoptosis; notably, NAT10 depletion abrogated the tumor-promoting effects of FAM117B overexpression. In conclusion, this study reveals the molecular mechanism by which FAM117B promotes HCC progression via forming a bidirectional regulatory loop with NAT10 and activating the JAK-STAT3 signaling pathway through acetylation modification, providing a novel potential target and theoretical basis for targeted therapy of HCC.
Background SLC25A45 belongs to the mitochondrial trimethyllysine carrier protein family. To date, its role in tumor development has not been fully elucidated. Previous studies have demonstrated its pro-tumor function in ovarian cancer; however, research on the expression characteristics, biological roles and underlying regulatory pathways of SLC25A45 in hepatocellular carcinoma (HCC) is limited. This study aims to explore the expression, functional roles, and regulatory pathways of SLC25A45 in HCC. Methods This study examined SLC25A45 expression and clinical relevance in HCC using publicly available transcriptomic data. SLC25A45 knockdown cell lines were constructed using PLC/PRF/5, Huh7, and Huh1 cells. Functional assays, including cell proliferation and colony formation assays, were then conducted. To investigate the effects of SLC25A45 knockdown on the malignant phenotypes of HCC cells in vitro, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses were performed to identify potential underlying mechanisms, which were subsequently validated by experimental assays. Results SLC25A45 was elevated in clinical HCC specimens, and high SLC25A45 expression was correlated with disease progression and poor overall survival (OS). In vitro functional assays demonstrated that SLC25A45 silencing reduced HCC cell proliferation and colony formation. Mechanistically, GSEA indicated that high SLC25A45 expression was significantly enriched in the p53 signaling pathways. SLC25A45 knockdown in HCC cells led to a significant increase in wild-type p53 protein expression, but a substantial decrease in mutant p53 expression. Conclusions SLC25A45 is a potential prognostic indicator and may drive HCC tumorigenesis and progression through the differential modulation of the p53 signaling pathways.
Kang Li, Yue-Kui Shen, Peng-Fei Wei et al.· Journal of Gastrointestinal...· 0 citations
Higher circ_0027446 expression was associated with larger tumor size, lymph node metastasis, advanced TNM stage, and shorter overall survival, and may contribute to tumor progression and immune escape-related changes, at least partly through the miR-6882-3p/HOXB9 axis.
Qing-Ye Zhao, Chen Qin, Jie Chai et al.· Journal of Molecular Histolo...· 0 citations
ABSTRACT Hepatocellular carcinoma (HCC) is a major cause of cancer‐related death worldwide. Although the nucleolar protein NOL12 has been implicated in HCC progression, its comprehensive expression patterns, clinical significance and regulation—particularly the potential involvement of miR‐1246‐5p and H3K27ac—are not fully understood, warranting further investigation. To analyse the expression pattern and clinical significance of NOL12, we integrated bulk RNA sequencing (bulk RNA‐seq) data (4264 HCC cases vs. 3145 non‐HCC cases), single‐cell RNA sequencing (scRNA‐seq) data (12 HCC samples) and spatial transcriptomics (ST) data from public databases including GEO, TCGA and GTEx. This integration was combined with in‐house immunohistochemistry (IHC) data from 394 pairs of HCC tissues and adjacent non‐tumour tissues. CRISPR screening was used to assess the effect of NOL12 depletion on HCC cell proliferation. Seven immune infiltration analysis methods (including CIBERSORT) were applied to the TCGA‐GTEx dataset to explore the association between NOL12 and the tumour immune microenvironment (TME). Gene ontology (GO) enrichment, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway and Gene Set Enrichment Analysis (GSEA) were performed based on NOL12‐associated genes involved in HCC initiation and progression. Additionally, chromatin immunoprecipitation sequencing (ChIP‐seq) data from Cistrome DB were used to predict and construct the miR‐1246‐5p–enhancer–NOL12 regulatory network. Potential high‐affinity drug molecules targeting NOL12 were screened via the Cancer Therapeutics Response Portal (CTRP) database and molecular docking. Multi‐dimensional analysis revealed significant upregulation of NOL12 in HCC (SMD = 0.64, 95% CI: 0.42–0.85; sROC AUC = 0.79). IHC validation confirmed higher NOL12 expression in HCC tissues (p < 0.0001, ROC AUC = 0.665). CRISPR screening showed that NOL12 depletion inhibited HCC cell proliferation. Mechanistically, NOL12 was enriched in the spliceosome pathway. ChIP‐seq identified an H3K27ac‐modified enhancer in the NOL12 promoter overlapping with miR‐1246‐5p binding sites, and miR‐1246‐5p expression positively correlated with NOL12 (r = 0.43, p = 0.018). Drug sensitivity prediction analysis showed that NOL12 protein exhibited significant sensitivity to BRD‐K71781559, MST‐312, IU1, BRD9876 and PRL‐3 inhibitor I, with favourable binding energies. NOL12 may be regulated by the putative miR‐1246‐5p/H3K27ac enhancer axis and promotes HCC progression through the spliceosome pathway, supporting its potential as a novel therapeutic target for HCC.
Li Xiao, Yu-Long Deng, Li-Na Liang et al.· IET Systems Biology· 0 citations
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