MXRA5 promotes the progression and metastasis of breast cancer via activation of the epithelial-to-mesenchymal transition pathway

Pan-Cancer Landscape of Interferon-Induced Protein 35 and Its Tumor-Promoting Role in Breast Cancer.

Functional studies demonstrated that IFI35 knockdown effectively suppressed BRCA cell proliferation, migration, and invasion, while promoting apoptosis, and is a potential therapeutic target for BRCA.

MX1 promotes gastric cancer cell migration via inhibiting ANXA2 ubiquitination and degradation.

Gastric cancer (GC) is a globally lethal malignancy, with invasion and metastasis driving treatment failure and poor prognosis. MX dynamin like GTPase 1 (MX1) shows tumor-specific functional heterogeneity, while its expression, biological functions and molecular mechanisms in GC remain unclear. Here, we explored MX1's clinical significance and its regulatory mechanism in GC cell migration. We integrated public databases and institutional paired clinical samples for bioinformatics analysis of MX1's correlation with clinical outcomes, and verified its pro-migratory effect via Transwell and wound healing assays. Co-immunoprecipitation/mass spectrometry (Co-IP/MS), immunofluorescence and ubiquitination assays were used to identify MX1-interacting proteins and dissect the underlying mechanism, and the Genomics of Drug Sensitivity in Cancer database was applied for chemosensitivity analysis. MX1 was aberrantly upregulated in GC tissues and served as an independent prognostic biomarker, with high expression associated with shortened overall, first-progression and post-progression survival. MX1 promoted GC cell migration and epithelial-mesenchymal transition pathway enrichment, and directly bound Annexin A2 (ANXA2) in the cytoplasm; both were co-enriched in endothelial and epithelial cells by single-cell sequencing. MX1 dose-dependently upregulated ANXA2 protein (without affecting its mRNA) by inhibiting NEDD4L/TRIM65-mediated ANXA2 ubiquitination and degradation, enhancing ANXA2 stability. Additionally, high MX1 expression correlated with increased paclitaxel sensitivity in GC patients based on database analysis, and CCK-8 assays confirmed that MX1 overexpression significantly reduced the paclitaxel IC50 in gastric cancer cells, supporting its potential as a predictive biomarker for paclitaxel efficacy. This study demonstrates that MX1 promotes GC cell migration by suppressing ANXA2 ubiquitination and degradation, highlighting the critical role of the MX1-ANXA2 axis in GC progression. These findings provide novel molecular targets and theoretical support for GC prognostic evaluation, individualized chemotherapy and targeted therapy.

DHRS2 regulates epithelial-mesenchymal transition in breast cancer cells

The role of SLC7A11 in regulating breast cancer brain metastasis

Brain metastasis in breast cancer patients represents an advanced and often fatal stage of disease, with survival typically less than one year following diagnosis. Despite therapeutic progress in primary tumors, effective treatments for breast cancer brain metastasis (BCBM) remain limited, highlighting the need for new mechanistic insights and therapeutic strategies. Our lab has recently found that SLC7A11 levels are significantly enriched in BCBM patient samples and are required for BCBM growth in vivo. SLC7A11, is a cystine/glutamate antiporter and is critical for glutathione (GSH) synthesis and protection against ferroptosis, a form of iron-dependent cell death. While it's function in ferroptosis resistance is well established, it's broader role in BCBM progression remains incompletely defined. Proteomic analyses of breast cancer cells overexpressing SLC7A11 revealed upregulation of extracellular matrix (ECM) and integrin-associated proteins, prompting investigation into regulation of ECM signaling pathways. In this study, we demonstrate that SLC7A11 overexpression significantly increases integrin [alpha]3, [alpha]6, and [beta]1 protein levels and focal adhesion kinase (FAK) activity, as evidenced by increased phosphorylation at tyrosine 397. Consistent with this data, using clonogenic survival assays, SLC7A11 overexpressing breast cancer cells showed resistance to FAK inhibitor induced cell death. In order to evaluate therapeutic potential of FAK inhibitors, we utilized an ex vivo brain slice model of BCBM. Treatment with clinically relevant FAK inhibitors including, PND-1186 and Defactinib resulted in significant tumor regression compared to controls. These findings indicate that FAK signaling contributes to BCBM tumor maintenance and that it's inhibition can effectively suppress tumor growth. Collectively, our results identify SLC7A11 as a non-canonical regulator of ECM/integrin-mediated FAK survival signaling in brain metastatic breast cancer cells. Targeting this axis may represent a promising strategy to enhance therapeutic vulnerability and improve outcomes in patients with breast cancer brain metastasis.

CD24 interacts with EDN1 to activate NFκB signaling driving triple-negative breast cancer tumor progression and paclitaxel resistance.

Breast cancer (BC) is the most common malignant tumor among women worldwide, and its chemotherapy resistance poses a major challenge in clinical treatment. Triple-negative breast cancer (TNBC) is a specific type of breast cancer that has attracted significant attention due to its extremely poor prognosis. The effectiveness of treatment and the prognosis for survival are significantly impacted by paclitaxel (PTX) resistance, a key chemotherapy medication for BC patients, particularly those with TNBC. CD24 is considerably overexpressed in PTX-resistant MDA-MB-231 cells and tissues, and it is directly linked to a bad prognosis for patients, according to this study's bioinformatics analysis and experimental confirmation. According to mechanistic research, CD24 suppresses MDA-MB-231 cell apoptosis while increasing invasion and proliferation by directly interacting with Endothelin-1 (EDN1) to activate the NFκB signaling pathway. Experiments both in vitro and in vivo demonstrate that CD24 knockdown dramatically reduces tumor development and increases PTX sensitivity. The CD24-EDN1-NFκB axis has a crucial role in PTX resistance in TNBC, according to this study, offering a new therapeutic target for treating chemotherapy resistance.

SPP1 promotes the metastasis of liver cancer cells through modulation of the MT1L/vimentin axis.

Tumor metastasis, a hallmark of cancer progression including hepatocellular carcinoma (HCC), is closely linked to poor prognosis. Therefore, strategies to suppress tumor metastasis remain an unresolved challenge for improving patient care. We identified that the oncogenic gene secreted phosphoprotein 1 (SPP1) is highly expressed in HCC tissues. A pseudogene-derived long non-coding RNA, metallothionein 1L (MT1L), was found to be negatively regulated by SPP1. Clinically, MT1L expression was reduced in HCC specimens, and its higher expression correlated positively with favorable prognosis. Notably, MT1L expression was inversely correlated with SPP1 expression in HCC. Mechanistically, SPP1 suppressed MT1L expression through the integrin signaling pathway. Overexpression of MT1L inhibited cell motility and lipid accumulation by repressing vimentin expression. Furthermore, rescue experiments demonstrated that MT1L was functionally involved in SPP1-mediated effects. Collectively, our findings reveal a novel association among the SPP1/MT1L/integrin/vimentin axis in HCC progression, suggesting that targeting this pathway may represent a potential therapeutic approach for HCC.