Objective/Introduction Cervical cancer is one of the most common malignant tumors of the female reproductive system. Radiotherapy is the primary treatment for advanced cervical cancer; however, tumor radioresistance limits its therapeutic efficacy, and the underlying mechanisms remain unclear. This study evaluated the relationship between the expression of Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) and radiosensitivity in cervical cancer cells. Methods Bioinformatics analyses were performed to assess CIP2A gene expression in cancers. Western blot analysis was used to determine protein expression levels in irradiated HeLa and SiHa cells. Colony formation assay, Cell Counting Kit-8 (CCK-8) proliferation assay, 4 ',6-diamidino-2-phenylindole (DAPI) staining, comet assay, and transmission electron microscopy detection were conducted to examine the regulatory effects of CIP2A on autophagy. Immunohistochemical staining was performed to validate these findings in vivo. Results and Discussion Bioinformatics analyses showed that CIP2A was overexpressed in multiple solid tumors. Silencing CIP2A reduced cell proliferation and colony formation while increasing radiation-induced DNA damage in HeLa and SiHa cells. Immunohistochemical analyses further demonstrated that CIP2A expression was closely correlated with the expression of key autophagy-related proteins. CIP2A knockdown increased the expression of autophagy-related proteins and the number of autophagic bodies, indicating induction of autophagy. Inhibition of beclin1 expression partially rescued the reduction in colony-forming ability caused by CIP2A silencing in cervical cancer cells. Conclusion Silencing CIP2A enhances the radiosensitivity of cervical cancer cells potentially by promoting autophagy. Future investigations into CIP2A-targeted therapies hold potential for improving the efficacy of radiotherapy in advanced cervical cancer.
Introduction Although MOB kinase activator 1A (MOB1A) is known to be involved in developmental processes and various malignancies, its specific contribution to the progression of Breast Cancer (BC) remains unclear. This study aimed to investigate the clinical significance, biological function, and potential molecular mechanisms of MOB1A in BC.Methods Integrative bioinformatics analysis was utilized to evaluate the clinical relevance and expression status of MOB1A in BC. To elucidate its biological function, MOB1A-depleted and MOB1A-overexpressing cell lines were established using lentiviral vectors. The impact of MOB1A on tumor aggressiveness was examined using CCK-8 proliferation assays, wound healing migration tests, flow cytometry, and xenograft mouse models.Results MOB1A expression was significantly upregulated in BC tissues and identified as an independent indicator of poor outcomes. Functional assays showed that MOB1A depletion markedly inhibited cell growth and motility in vitro, which was consistent with the observations from in vivo experiments. Conversely, upregulation of MOB1A promoted these malignant behaviors. Furthermore, bioinformatics analysis suggests that MOB1A is associated with the activation of the IL6/JAK/STAT3 signaling pathway and the regulation of immune infiltration.Discussion These findings collectively suggest that MOB1A exerts a pro-tumorigenic role in BC and may modulate tumor progression and the tumor microenvironment, although further mechanistic validation is warranted.Conclusion This study identifies MOB1A as a highly expressed oncogene associated with poor clinical outcomes in BC. MOB1A facilitates tumor progression and metastasis, potentially through the regulation of the IL6/JAK/STAT3 pathway and the tumor immune microenvironment.
Abstract: Hepatocellular carcinoma (HCC) remains one of the most important causes of cancer-related death worldwide due to late diagnosis, chronic liver disease, and the highly immunosuppressive tumour microenvironment that favors immune escape and therapeutic resistance. Recently, immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte- associated antigen-4 (CTLA-4) have significantly improved the treatment of advanced HCC, especially when used in combination therapy, resulting in stronger antitumour immune responses. Several major clinical trials such as IMbrave150, HIMALAYA and Check Mate-9DW have confirmed that immune checkpoint inhibitor combinations are valuable first-line treatment options for unresectable HCC. However, primary and acquired resistance remain a major challenge to achieving durable clinical responses, and new treatment strategies are needed. Other immune checkpoint molecules, such as lymphocyte activation gene-3 (LAG-3) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), have demonstrated significant potential as novel targets for immunotherapy, due to their role in T-cell exhaustion, natural killer cell dysfunction, and adaptive immune escape. This review highlights the molecular mechanisms, preclinical and clinical evidence, and therapeutic potential of CTLA-4/PD-1, LAG-3, and TIGIT inhibitors, particularly in dual and triplet combination approaches. It also discusses mechanisms of resistance, patient stratification using biomarkers, and the safety profile of these combinations, including their use in patients undergoing liver transplantation. Finally, we explore emerging opportunities and ongoing challenges in the field of precision immunotherapy and discuss future directions to improve clinical outcomes in patients with HCC.
Introduction: Our preliminary findings indicate that bioinformatic analysis of the Cancer Genome Atlas (TCGA) database reveals a significant upregulation of Mitotic-Spindle Organizing Protein 1 (MZT1) in Lung Adenocarcinoma (LUAD) cohorts compared to normal controls; however, the underlying molecular mechanisms remain elusive. To investigate the expression of MZT1 in LUAD cells, its role in tumor invasion and metastasis, and its potential as a biomarker for LUAD. Methods: The differential expression of MZT1 at both mRNA and protein levels between LUAD tissues and adjacent normal tissues was analyzed using the TCGA, TIMER, and UALCAN databases. Differentially expressed genes between high- and low-MZT1 expression groups were screened using R packages and Gene Set Enrichment Analysis (GSEA), followed by biological pathway enrichment analysis. Quantitative real-time Polymerase Chain Reaction (qPCR) was employed to detect MZT1 expression levels in LUAD cell lines. MZT1-knockdown cell lines were constructed, and functional validation was performed using Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays. Results: Bioinformatics analysis confirmed MZT1 is highly expressed in LUAD tissues, with expression levels varying significantly by patient gender, smoking status, T-stage, and survival duration. Univariate and multivariate Cox regression analyses identified MZT1 as an independent prognostic factor for LUAD, with ROC analysis suggesting a potential diagnostic value within the TCGA cohort (AUC = 0.712). Higher MZT1 expression correlated with poorer Overall Survival (OS) and Disease-Specific Survival (DSS). GO/KEGG and GSEA analyses linked MZT1 to cell cycle regulation, oocyte meiosis, and cell cycle checkpoint signaling. MZT1 expression positively correlated with tumor mutational burden and showed significant associations with reduced immune infiltrates. Cell experiments show that knockdown of MZT1 can inhibit LUAD cell proliferation, colony formation, migration and invasion, as well as the Epithelial-Mesenchymal Transition (EMT) process. Discussion: Although MZT1 is recognized as a fundamental component of the γ-Tubulin Ring Complex (γ-TuRC), its role in LUAD remains unexplored. Our bioinformatic and clinical analyses revealed that MZT1 is significantly upregulated in LUAD and is closely associated with advanced clinical stages and poor overall survival, and it serves as an independent prognostic factor with potential diagnostic value. Mechanistically, MZT1 is strongly enriched in cell cycle regulation pathways and correlates negatively with multiple immune infiltrating cells, suggesting it may promote tumor progression and facilitate immune evasion. Notably, the positive correlation between MZT1 expression and TMB, combined with suppressed immune infiltration, highlights a unique immune phenotype characterized by high genomic instability and effective immune exclusion. In vitro experiments demonstrated that MZT1 knockdown significantly inhibits LUAD cell proliferation, migration, invasion, and EMT, indicating its dual role in driving primary tumor growth and metastatic potential. However, this study is limited by the lack of in vivo validation and detailed molecular mechanisms. Future studies utilizing animal models and multi-omics approaches are warranted to elucidate the precise downstream signaling pathways and therapeutic potential of MZT1 in LUAD. Conclusion: MZT1 is highly expressed in LUAD tissues and is associated with immune infiltration in tumors. Functional enrichment and in vitro experiments suggest that MZT1 may promote LUAD progres-sion by regulating cell cycle-related pathways and EMT, thereby driving cell proliferation and metastasis.
Background: Ovarian cancer is the most lethal gynecological malignancy, and acquired resistance to chemotherapy and targeted therapy is a central cause of treatment failure. The WEE1 inhibitor AZD1775 (adavosertib) has shown clinical activity in ovarian cancer, particularly in tumors with TP53 dysfunction, but acquired resistance frequently emerges, and its molecular basis remains incompletely understood. This study aims to identify a conserved, cross-species gene signature associated with the AZD1775-resistant state, to characterize its relationship with the Tumor Immune Microenviron-ment (TIME) and patient prognosis, and to nominate candidate drugs for combination testing. Methods: Transcriptomic data from a self-established murine AZD1775-resistance model (ID8 vs ID8R; RNA-seq, GSE313926) and from publicly available human AZD1775-resistant ovarian cancer cells (ES-2 vs ES-2R clones; GSE142124) were integrated. Differentially Expressed Genes (DEGs) were intersected across models, Weighted Gene Co-Expression Network Analysis (WGCNA) was applied to the ID8/ID8R data, and a Protein–Protein Interaction (PPI) network was used to prioritize connected candidates. In the TCGA Ovarian Cancer (TCGA-OV) cohort, ESTIMATE and five immune deconvo-lution algorithms (CIBERSORT, EPIC, TIMER, MCP-counter, and quanTIseq) were used to estimate stromal/immune admixture. The prognostic associations were assessed in Kaplan-Meier Plotter. Candi-date drugs were prioritized from CellMiner using a pre-specified effect-size threshold, and drug combi-nations with AZD1775 were tested in ID8R cells by CCK-8 with Chou–Talalay analysis. Results: A nine-gene signature (VCAN, RNASEL, PROS1, TNFRSF9, PXDN, KCNH1, KLF11, ATF3, and CDK15) was consistently upregulated across resistant models and within the resistance-associated WGCNA module. ESTIMATE and deconvolution analyses associated the signature with stromal/CAF and endothelial compartments, with weaker, method-dependent associations with immune-cell fractions. The nine-gene score was associated with overall survival, with heterogeneous direction for individual genes (VCAN, ATF3, CDK15, KLF11, and PXDN adverse; TNFRSF9, KCNH1, RNASEL protective). CellMiner drug sensitivity prediction and in vitro validation revealed that cell lines with high expression of the core gene set were more sensitive to Bleomycin, Lenvatinib, and Dasatinib; combinations with AZD1775 produced additive-to-synergistic effects under the standard Chou–Talalay grading (CI < 0.9) in ID8R. These agents are nominated as candidate combination partners for experimental testing. Discussion: Cross-species integration of a murine isogenic resistance pair with independent human re-sistant clones identifies a nine-gene panel associated with the AZD1775-resistant state and with re-sistance-coupled stromal–myeloid remodeling, adverse prognosis and differential drug sensitivity in ovarian cancer. Because the panel was derived by association and several of its genes are predominantly expressed by stromal, myeloid, and activated immune cells rather than malignant cells, it should be regarded as a cross-compartment, resistance-associated marker rather than a set of causal drivers; func-tional perturbation and validation in independent resistant models are required. Nevertheless, the panel may help stratify patients for WEE1-inhibitor therapy and prioritize candidate combination partners for experimental testing. Conclusion: Cross-species integration nominates a nine-gene signature associated with the AZD1775-resistant state and resistance-coupled stromal–myeloid remodeling in ovarian cancer. The signature is a candidate marker of resistance-associated states and of drug response.
