Aug 2026· Oncology Letters· Vol 32, pp. 1-13· 0 citations· 51 references
Medicine
TL;DR
It is discovered that STXBP1 regulates global gene expression and alternative splicing profiles in MDA-MB-231 cells by modulating 111 differentially expressed genes and 1,161 regulated alternative splicing events.
Abstract
As the most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC) is frequently treated with radiotherapy. Downregulation of syntaxin binding protein 1 (STXBP1) gene expression is notably associated with poor prognosis in patients with breast cancer and its protein expression level is associated with tumor radioresistance. However, the precise molecular mechanisms by which STXBP1 regulates breast cancer pathogenesis and radiotherapy resistance remain to be elucidated. In the present study, STXBP1 was overexpressed in MDA-MB-231 cells to investigate its effects on cell proliferation and apoptosis. Transcriptomic sequencing (RNA-sequencing; RNA-seq) was performed to identify differentially expressed genes and alternative splicing events regulated by STXBP1. Additionally, a publicly available RNA-seq dataset (GSE189495) associated with breast cancer radiotherapy, including three fractionally irradiated 20 Gy and three age-matched control MCF-7 cell samples were analyzed to identify radiotherapy-associated alternative splicing alterations. Integrated analysis of these two datasets was conducted to explore the potential mechanisms underlying STXBP1-mediated radiotherapy response in breast cancer. Key gene expression changes and alternative splicing events were validated using reverse transcription-quantitative (RT-q) PCR. In MDA-MB-231 cells, the overexpression of STXBP1 notably inhibited cell proliferation and enhanced levels of apoptosis. Through an analysis of RNA-seq data, the present study discovered that STXBP1 regulates global gene expression and alternative splicing profiles in MDA-MB-231 cells by modulating 111 differentially expressed genes and 1,161 regulated alternative splicing events. STXBP1 plays a key role in regulating the splicing patterns of numerous DNA repair-related genes, including USP48 and PLEC. In addition, the present study conducted an overlap analysis on the transcriptome data from radiotherapy-treated MCF-7 cells alongside the dataset generated in the present study, which revealed 21 alternative splicing events associated with radiotherapy. Notably, these include the DNA repair-related gene UBE2I, and its expression pattern has been confirmed through RT-qPCR. The present study systematically delineated the downstream targets and functional mechanisms of STXBP1 in breast cancer cells, revealing its antitumor molecular role. Moreover, STXBP1 may be associated with radiation sensitivity by regulating the alternative splicing of genes associated with DNA repair. These molecular targets, such as UBE2I, hold potential as novel therapeutic avenues for breast cancer treatment, particularly for TNBC.
Objective Chromosomal instability (CIN) drives genomic structural variants (such as amplifications and deletions) and promotes tumor progression. Long noncoding RNAs are known to participate in key biological processes and CIN regulation. Our previous study demonstrated that the highly expressed lncTRDMT1–5 serves as a novel prognostic biomarker in breast cancer; however, its underlying mechanisms require further investigation. Methods LncTRDMT1–5 expression was knocked down in MDA-MB-231 cells, followed by chromosomal microarray analysis (CMA). Expression levels of lncTRDMT1–5 were examined in breast cancer cells and tissues via RT-PCR. Chromatin immunoprecipitation was used to detect H3K27 acetylation in the promoter region. RNA pull-down was performed to identified interactions with the MSRB3 protein. Cell proliferation was evaluated by EdU assay, DNA damage was assessed by γH2AX immunofluorescence, and cell cycle distribution was analyzed by flow cytometry. EMT-related protein expression and cell cycle regulators were examined by western blotting. Results LncTRDMT1–5 was significantly upregulated in breast cancer cells and tissues, with H3K27 acetylation detected in its promoter. Downregulation of lncTRDMT1–5 induced CNVs across different chromosomes. Overexpression of lncTRDMT1–5 promoted cell proliferation, DNA damage, and EMT-related protein expression. RNA pulldown confirmed the relationship between lncTRDMT1–5 and MSRB3 protein. Mechanistically, lncTRDMT1–5 regulated cell cycle arrest by inhibiting p53 and inducing the expression of cell-division cycle protein 20 homologue (CDC20). Conclusion Overexpression of lncTRDMT1–5 in breast cancer induces CIN and tumor progression by promoting EMT process and increasing MSRB3, p53 and CDC20 protein expression. Targeting this molecular pathway may offer novel therapeutic strategies and improve prognostic evaluations.
Qi Chen, Yunpeng Chen, Hui Yang et al.· Frontiers in Oncology· 0 citations
Metastatic breast cancer with complex molecular mechanisms of progression accounts for most cancer related deaths in women. To improve diagnosis and drug development, it is important to identify novel biomarkers and critical molecular pathways involved in tumor initiation and progression. Here, we profiled and analyzed the expression of long non-coding RNAs (lncRNAs) from three distinct stages of tumor initiation and progression (hyperplasia, adenoma, and carcinoma). We performed RNAseq on tumor and mammary epithelial cells derived from ROSAmT/mG tumor and non-tumor mice. We identified 1913 differentially expressed protein coding genes and 324 lncRNAs in breast cancer cells of all stages compared with normal mammary epithelial cells. Pearson correlation analysis correlated 93 differentially expressed lncRNAs with protein coding genes, providing a comprehensive lncRNA-protein coding genes co-expression network. Among them, we focused on Gm19303 which was paired with the differentially expressed protein coding gene, transcriptional repressor GATA binding 1 (Trps1), and identified its human counterpart as LINC00536. Both LINC00536 and TRPS1 are only overexpressed in breast cancer and correlate with poor prognosis of patient from the TCGA and GTEx databases. Single cell RNAseq data from the Atlas of Human breast cancers further confirmed that TRPS1 is upregulated in human breast cancer compared to normal human mammary tissue with highest expression in ER+ subgroup. In summary, our study explored the potential role of lncRNAs in breast cancer initiation and progression. Implications statement Our findings imply that human LINC00536/TRPS1 serves as a novel and early biomarker of cancer progression and a potential therapeutic target for breast cancer.
Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy with high incidence and mortality. Dysregulated RNA-binding proteins (RBPs) have been implicated in various cancers, yet their role in regulating tumor suppressors in CRC is underexplored. This study analyzed TCGA gene expression data to identify prognostic markers and used CLIP-seq data to uncover RBPs putatively binding to TP53, RB1, and PTEN. Functional enrichment via Gene Ontology (GO) and MSigDB Hallmark pathways suggested involvement in mRNA processing, Myc Targets V1, and Unfolded Protein Response. Univariate Cox regression analyses identified high expression of NOP56, EIF4A3, and IGF2BP1 as associated with poor survival, while high RBM47 expression was linked to improved prognosis; these findings were validated using Kaplan-Meier survival curves. However, multivariate Cox regression analysis was not performed, and independent prognostic validation is required. ROC analysis further indicated that several RBPs could distinguish tumor from normal tissues. Importantly, these AUC values were derived from the TCGA discovery dataset and require independent external validation before any diagnostic application can be considered. Drug sensitivity analyses using GDSC and CCLE datasets revealed exploratory and unadjusted associations between elevated NOP56, FBL, and FUS expression and increased sensitivity to Irinotecan, Nilotinib, and Raf265. A multi-cohort integrated analysis and qRT-PCR confirmed upregulation of selected RBPs in CRC tissues and cell lines. Importantly, these CLIP-seq interactions reflect physical binding potential rather than direct functional regulation of target gene expression. Overall, 22 RBPs were identified as candidate binding-associated regulators of key tumor suppressors, and seven RBPs involved in prominent pathways were identified as candidate prognostic biomarkers requiring further validation in independent cohorts before any clinical application can be considered in CRC, although these findings remain exploratory and require further functional validation.
A. Asadi, Mehrdad Hashemi, M. Peymani et al.· Discover Oncology· 0 citations
GPR19 functions as a novel oncogenic driver and clinically relevant biomarker in breast cancer, particularly in TP53-mutant and TNBC subsets, and was significantly upregulated in TP53-mutant breast cancer, primary tumors, and especially TNBC.
Jihan Qiu, Cheng Tian, Hanzhi Li et al.· Frontiers in Bioscience· 0 citations
It is suggested that TP53AIP1 may serve as a potential prognostic biomarker and tumor-suppressive candidate in breast cancer, with its effects at least partly associated with MAPK pathway attenuation.
Meihai Deng, Xueting Wu, J. Bai et al.· Discover Oncology· 0 citations
Triple-negative breast cancer (TNBC) is a major cause of cancer mortality, with distant metastases, particularly to the lungs, presenting a significant clinical challenge. While epigenetic mechanisms like DNA methylation (DNAm) are known to influence TNBC progression, their association with lung metastasis remains underexplored. To address this gap, we analyze epigenomic and transcriptomic profiles from TNBC cells, xenograft models, and patient cohorts. DNAm profiling of primary tumors, lymph nodes, and lung metastases in our xenograft model reveals significant genome-wide hypomethylation in lung lesions, consistent with findings on patient samples from the AURORA US cohort. Promoter-methylation changes are enriched in pathways linked to invasion and proliferation, and transcriptomic integration identifies 22 regulated genes, with outcome effects varying according to the histone chromatin context. In vitro demethylation in TNBC cells partially recapitulates the expression changes of several candidate genes. Beyond promoters, enhancer elements are also dysregulated in lung metastases, potentially affecting the expression of their associated genes. Among others, elevated AK1, TPI1, and ENO1 expression correlates with a higher risk of lung dissemination in primary TNBC tumors. These findings highlight DNAm alterations associated with TNBC lung colonization and identify candidate prognostic markers, emphasizing DNAm reprogramming as a feature of breast-to-lung-metastatic progression.
Andrés F Bedoya-López, Sandra Íñiguez-Muñoz, Javier I. J. Orozco et al.· Communications Biology· 0 citations
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