IUBMB Life最新文献

Disco interacting protein 2 homolog B (DIP2B) is a protein-coding gene implicated in various biological processes, including embryonic development, cell cycle regulation, DNA repair, and transcriptional regulation. While its precise role in cancer remains largely unknown, emerging evidence suggests its potential involvement in tumorigenesis. In this study, we provide a comprehensive analysis of DIP2B in cancer, exploring its expression patterns, molecular functions, and potential clinical implications across different cancer types. We examined the expression, dysregulation, and prognostic significance of DIP2B. The mRNA and protein expression status of DIP2B was determined using data from TCGA, GTEx, and UALCAN. Using TCGA database data, we investigated associations between DIP2B expression and gene mutations, survival outcomes, DNA methylation, immune cell infiltration, tumor mutation burden (TMB), and drug sensitivity. High DIP2B expression was associated with poor overall survival (OS) in BRCA, KICH, LUAD, MESO, SARC, and THCA, but with improved OS in KIRC. For disease-specific survival (DSS), elevated DIP2B levels correlated with adverse outcomes in ACC, MESO, and UVM. GO and KEGG analyses implicated DIP2B in cytoskeleton organization, MAPK signaling, and ubiquitin-dependent protein catabolism. Experimental validation in KIRC cells showed that DIP2B knockdown significantly reduced cell proliferation and migration. Conversely, DIP2B exhibited oncogenic functions in LUAD cells. These findings suggest DIP2B may serve as a potential prognostic and diagnostic biomarker, displaying a unique tumor-suppressive role in KIRC progression.

Cervical cancer remains a significant challenge to global health, necessitating the development of reliable clinical prognostic models to predict patient survival outcomes with accuracy. This study aims to develop an mRNA signature model based on tumor immune infiltration characteristics of cervical cancer. By employing RNA sequencing technologies at both tissue and single-cell resolutions, a survival predictive gene signature was constructed for cervical cancer through the application of machine learning methods. To further validate the key prognostic genes identified in the prognostic signature, we performed additional experiments, including tissue microarray (TMA) analysis and in vitro assays. Our developed signature model comprised nine genes, which ranks at the top tier when compared to previously published mRNA signature models. Gamma-interferon-inducible lysosomal thiol reductase (IFI30) emerged as a critical prognostic marker, validated externally through immunohistochemistry (IHC) and multiplex immunohistochemistry staining (mIHC) on cervical cancer TMAs. Notably, IFI30 exhibited pronounced expression in macrophages compared to other cell types within the tumor microenvironment (TME). We further investigated the potential role of IFI30 in regulating macrophage polarization. Specifically, a reduced expression of IFI30 in macrophages co-cultured with HeLa cells induced a polarization transition from the M2 to the M1 phenotype. In conclusion, we have successfully established a prognostic model on the basis of tumor immune infiltration characteristic of cervical cancer, highlighting IFI30 as a pivotal prognostic marker potentially involved in macrophage polarization. Future investigation is required to explore the underlying mechanisms for the advancement of therapeutic strategies in cervical cancer.

Osteosarcoma (OS) is an uncommon malignancy with stagnant survival rates over the past four decades and early-stage metastasis, predominantly affecting children and adolescents. This study identified significant metabolic differences between metastatic and non-metastatic OS samples through bioinformatics analysis, highlighting key processes such as cell proliferation, mitochondrial assembly, and changes in mitochondrial membrane permeability. Among differentially expressed genes, Pleckstrin Homology And FYVE Domain Containing 1 (PLEKHF1) was the most significantly downregulated in metastatic OS samples. Functional experiments demonstrated that PLEKHF1 overexpression in Saos-2 and U2OS cells induced mitochondrial dysfunction, evidenced by increased mtROS levels, decreased mitochondrial membrane potential, and altered cytochrome C distribution. Additionally, PLEKHF1 overexpression inhibited OS cell viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT), while promoting apoptosis. Conversely, knockdown of PLEKHF1 had the opposite effects on Saos-2 and U2OS cells. In vivo, PLEKHF1 overexpression reduced tumor growth and lung metastasis in a mouse model. Conversely, PLEKHF1 knockdown ameliorated Rotenone-induced mitochondrial dysfunction and mitophagy, partially reversing the suppressive effects of Rotenone on OS cell aggressiveness. These findings suggest that PLEKHF1 could serve as an anti-tumor factor by inducing mitochondrial dysfunction, thereby inhibiting OS growth and metastasis. The study highlights the potential of PLEKHF1 as a therapeutic target for managing osteosarcoma, providing valuable insights into the role of mitochondrial dysfunction in OS pathogenesis.

Bone cancer remains a life-threatening malignancy predominantly affecting pediatric and adolescent populations, with tyrosine kinase inhibitors (TKIs) emerging as promising therapeutic agents; however, their clinical utility is limited by poor bioavailability, systemic toxicity, and inadequate tumor targeting. Recent advancements in nanocarrier-based delivery systems have significantly mitigated these limitations by enhancing targeted accumulation of TKIs at tumor sites, reducing off-target effects, and enabling controlled drug release. Various nanocarrier platforms, including liposomes, polymeric nanoparticles, micelles, dendrimers, metal- and metal oxide-based nanoparticles, carbon-based carriers, polymeric implants, and hydroxyapatite-based systems, have been systematically evaluated for their efficacy in delivering TKIs for bone cancer therapy. This review further examines the impact of nanoparticle size on cellular uptake and tumor penetration, with emphasis on liposomal and proteinaceous carriers (albumin-bound and transferrin-conjugated nanoparticles) that optimize tumor selectivity while minimizing systemic toxicity. Inorganic nanocarriers such as gold, silver, and metal oxides also demonstrate potential for multimodal therapeutic and diagnostic applications. Notwithstanding these advances, challenges including drug resistance, toxicity, and regulatory barriers remain, necessitating ongoing efforts to optimize nanocarrier formulations. This comprehensive review provides critical insights into the evolving landscape of nanotechnology-driven TKI delivery strategies aimed at enhancing therapeutic outcomes in bone cancer management.

Lung cancer is a severe malignant disease and causes plenty of deaths each year. The survival and prognosis are disappointing for patients with recurrence or metastasis. This is partially due to the lack of mechanisms underlying lung cancer. The ZEB1 gene was reported to promote progression in lung cancer. However, the mechanism of ZEB1 in lung cancer is a puzzle. ZEB1 and WNT7B were expressed more strongly in lung cancer cells. In clinical lung cancer tissues, ZEB1 was also overexpressed compared to the adjacent normal tissues. ZEB1 knockdown (ZEB1-KD) inhibited the activation of Wnt/β-catenin signaling. However, overexpression of WNT7B alleviated this inhibition. Furthermore, ZEB1 was shown to regulate the expression of WNT7B, and WNT7B was the bridge between ZEB1 and Wnt signaling. Cell proliferation and invasion ability were inhibited by ZEB1-KD, which was reversed by WNT7B overexpression. This regulation was supported by the expression patterns of PCNA, E-cadherin, and N-cadherin. In addition, much more cell apoptosis was induced in ZEB1-KD cells treated with Docetaxel compared to that without ZEB1-KD. This induction was reversed when WNT7B was overexpressed. Consistently, the IC50 value in the ZEB1-KD/Docetaxel group was much lower than that in the ZEB1-KD or Docetaxel alone group. In contrast, WNT7B overexpression increased the IC50 value of Docetaxel. In conclusion, ZEB1 positively regulates Wnt/β-catenin signaling in lung cancer and contributes to cancer progression. ZEB1 knockdown increases the efficacy of Docetaxel in lung cancer.

The development of acquired drug resistance in breast cancer (BC) significantly compromises treatment efficacy and patient survival, yet the underlying molecular mechanisms remain completely understood. In this study, we investigated the role of the Hippo signaling pathway and its regulatory factor, LIM Domain Only 4 (LMO4), in the acquired Adriamycin (ADR)-resistant MCF-7 (AdrR) cells. Using a combination of bioinformatics and experimental approaches, we demonstrated that AdrR cells exhibit defective apoptosis upon ADR treatment, characterized by abnormal expression of apoptotic proteins such as BAX and BCL2. RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) revealed significant dysregulation of the Hippo pathway in AdrR cells compared to parental MCF-7 cells, suggesting its involvement in mediating drug resistance. Further experiments showed that small interfering RNA (siRNA)-mediated knockdown of LMO4 (siLMO4) altered the expression of apoptotic proteins and partially restored ADR sensitivity in AdrR cells. Mechanistically, LMO4 was found to modulate the Hippo pathway, as evidenced by changes in the nuclear translocation of YAP and the phosphorylation levels of key Hippo pathway components (MST1/2 and YAP). Inhibition of the Hippo pathway using a Lats kinase inhibitor further confirmed its role in regulating drug resistance. Our findings highlight the critical involvement of the LMO4-Hippo signaling axis in ADR resistance and propose LMO4 as a potential therapeutic target for reversing chemoresistance in BC. This study provides novel insights into the molecular mechanisms of drug resistance and offers a foundation for future research aimed at improving treatment strategies for ADR-resistant breast cancer.

Three human bulk RNA sequencing (RNA-seq) datasets from the GEO database, comprising liver tissues from 76 patients with hepatic ischemia–reperfusion injury (IRI) and 80 controls, were analyzed to identify differentially expressed genes related to cellular senescence (DEG-CSRGs). A total of 19 DEG-CSRGs were identified out of 866 cellular senescence-related genes, and key hub genes (e.g., JUN, FOS, ATF3) were subsequently screened. In parallel, a single-cell RNA sequencing (scRNA-seq) analysis of a mouse hepatic IRI model was conducted, profiling 4998 immune cells from control and IRI liver tissues. The analysis revealed the central roles of macrophages, monocytes, and neutrophils in the IRI process, with significant upregulation of hub gene expression in these immune cell populations. Pseudotime trajectory and intercellular communication analyses further elucidated the dynamic transitions and interactions among immune cells during IRI progression. Drug-gene interaction prediction indicated fluoxetine (FLX) as a potential therapeutic candidate, and its binding affinity to hub genes was supported by molecular docking and molecular dynamics simulations. Bioinformatics predictions were experimentally validated using in vivo mouse models (n = 5 per group) and in vitro RAW264.7 macrophage cell assays (qPCR: n = 6 per group; Western blot: n = 3 per group), confirming that FLX mitigated liver injury and suppressed the expression of cellular senescence-related factors.

Intervertebral disc degeneration (IVDD) is a common degenerative disorder affecting the spine. Ferroptosis and cellular senescence are key pathological features driving IVDD progression, but the mechanisms involved in their regulation remain incompletely understood. While circular RNAs (circRNAs) have been implicated in nucleus pulposus cells (NPCs) function, the specific role of circZNF418 in IVDD has not been explored. In this study, we aimed to investigate the function and mechanism of circZNF418 in IVDD, focusing on its impact on oxidative stress-induced ferroptosis and senescence in NPCs. NPCs were treated with tert-butyl hydroperoxide to mimic oxidative stress during IVDD progression. The levels of malondialdehyde (MDA) and glutathione (GSH) were quantified using commercial kits, and senescence was assessed using SA-β-gal staining. Gene and protein expression was analyzed using qPCR, Western blotting, immunofluorescence, and immunohistochemistry. RNA pull-down and immunoprecipitation were used to examine interactions among circZNF418, HuR, and SIRT6. circZNF418 levels were found to be lower in degenerative nucleus pulposus tissues, associated with increased ferroptosis and cellular senescence. circZNF418 expression declined in response to oxidative stress and was correlated with increased NPC senescence and ferroptosis. Overexpression of circZNF418 protected NPCs from oxidative damage, while its knockdown exacerbated senescence and ferroptosis. Silencing of SIRT6 partially reversed the protective effects of circZNF418 overexpression. Additionally, both circZNF418 and SIRT6 were shown to bind to HuR, with circZNF418 promoting SIRT6 expression, which was reversed by HuR silencing. The findings indicate that circZNF418 regulates NPC senescence and ferroptosis by upregulating SIRT6. A novel signaling pathway, the novel circZNF418/HuR/SIRT6 axis, was identified, showing its potential in IVDD therapy, while circZNF418 was identified as a potential target, thus providing new diagnostic biomarkers and the development of effective treatments for IVDD.