This study aimed to elucidate the role and mechanism of CLDN1 in regulating migration and metastasis in triple‑negative breast cancer (TNBC). In vivo, an orthotopic TNBC model was used to evaluate circulating tumor cells and lung metastasis; in vitro, cell migration, F‑actin organization, and protein expression were examined in cultured TNBC cells. CLDN1 was knocked down or overexpressed via lentiviral constructs, and Ezrin was silenced by siRNA in CLDN1‑overexpressing cells. Pharmacological targeting of CLDN1 with PDS‑0330 specifically reduced migration in MDA‑MB‑468 cells but not in MDA‑MB‑231 cells; knock-down and knock‑in experiments further confirmed that CLDN1 critically determines the migratory and metastatic capacity of TNBC cells with high CLDN1 expression. Analysis of Ezrin and its interaction with podocalyxin revealed that Ezrin significantly contributes to CLDN1‑promoted migration, and our data also indicated that CLDN1 facilitates Src signaling activation. Collectively, these findings demonstrate that in TNBC with high CLDN1 expression, CLDN1 plays a pivotal role in regulating migration and hematogenous metastasis, likely through upregulating the Src/Ezrin pathway.
Background Neuroblastoma (NBL) prognosis remains poor in high-risk cases. Ferroptosis is a promising therapeutic target, but its regulation in NBL is unclear. This study investigates GINS1's role in NBL ferroptosis.Methods Bioinformatics analysis (GSE49710, GSE73517, TARGET) assessed GINS1 expression and prognosis. In vitro, GINS1 was knocked down in SH-SY5Y and SK-N-SH cells. Proliferation (CCK-8), migration (Transwell), apoptosis, and ferroptosis markers (lipid peroxidation, Fe2+, ACSL4, p-YAP) were evaluated. Rescue experiments involved ACSL4 overexpression.Results GINS1 knockdown in SH-SY5Y and SK-N-SH cells inhibited proliferation (60% reduction in SH-SY5Y cells and 55% in SK-N-SH cells, p < 0.001), migration (2.1-fold decrease in SH-SY5Y cells and 1.8-fold decrease in SK-N-SH cells, p < 0.001), and induced ferroptosis, evidenced by elevated lipid peroxidation (2.5-fold MDA increase, 1.8-fold Fe2+ increase, p < 0.001), upregulation of ACSL4, and increased p-YAP. Mechanistically, GINS1 ablation activates the Hippo pathway (evidenced by increased p-YAP and elevated p-YAP/YAP ratio), leading to YAP inactivation and subsequent derepression of ACSL4, thereby promoting ferroptosis. Rescue experiments confirmed that ACSL4 overexpression in GINS1-overexpressing cells antagonized tumor-promoting effects.Conclusion GINS1 suppresses ferroptosis via Hippo pathway inhibition and YAP activation, leading to ACSL4 repression. GINS1 is a potential prognostic biomarker and therapeutic target in high-risk NBL.
Background Triple-negative breast cancer (TNBC) is prone to immune escape, and the synergistic mechanism of kynurenine, AhR, and EMT remains unclear.Methods TNBC cell lines and 4T1 orthotopic breast cancer mice were used for molecular, cellular, and in vivo intervention experiments.Results Kynurenine induced EMT in an AhR-dependent way, promoted cell migration and invasion, upregulated CCL2/CCL22, and inhibited the function of CD8⁺GrB⁺ T cells. Snail overexpression promotes H3K4me3 histone modification at IDO1 and TDO2 promoters to epigenetically amplify tryptophan metabolic enzyme expression. The AhR antagonist CH-223191 blocked the loop and reversed tumor immune escape.Conclusion This study demonstrates that the kynurenine-AhR-EMT positive feedback loop drives immune escape in TNBC, providing a rationale for combined targeted therapy.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, its progression and treatment heterogeneity are mainly influenced by driver gene and tumor micro-environment (TME) interactions. Nevertheless, the mechanisms of this process at the single-cell level remain unclear. This study integrated TCGA and multi-center single-cell transcriptome data to identify a 575 genes HCC-specific core set, developing a single-cell “oncogene scoring” system to quantify individual carcinogenic activity. This score is significantly elevated in malignant and proliferative T cells and is closely associated with metabolic reprogramming, aberrant cell‒cell communication, and immunosuppressive phenotypes. Based on these characteristics, we constructed a machine learning-based Random Survival Forest (RSF) prognostic model validated in multiple independent cohorts, which classifies patients into distinct risk subtypes. The high-risk group exhibits genomic instability, increased tumor stemness, and immune evasion, while the low-risk group was more sensitive to drugs such as sorafenib. This study highlights the potential pathways by which high oncogenic activity is associated with HCC progression, suggesting a profound link with single-cell metabolic‒immune crosstalk. The constructed RSF model offers a promising computational framework for risk stratification and provides hypothesis-generating insights that may inform future personalized treatment strategies for HCC patients.
Incomplete radiofrequency ablation (iRFA) exposes residual hepatocellular carcinoma (HCC) cells to sublethal thermal stress, which triggers metabolic adaptations that support cell survival. In this study, we demonstrate that iRFA significantly enhances glucose uptake in HCC cells, contributing to the suppression of intracellular reactive oxygen species (ROS) and promoting cell viability. Mechanistically, this effect is mediated by the translocation of GLUT4 from the cytoplasm to the plasma membrane, rather than changes in total GLUT4 expression. GLUT4 redistribution under thermal stress facilitates rapid glucose uptake, providing energy and biosynthetic intermediates necessary for survival under adverse microenvironmental conditions. Inhibition of GLUT4-mediated glucose uptake increases ROS accumulation and reduces cell survival, highlighting its critical role in redox homeostasis. Collectively, our findings reveal an iRFA-GLUT4-glucose uptake axis as a key metabolic adaptation pathway that enables residual tumor cells to survive sublethal thermal stress, suggesting that targeting GLUT4 dynamics may represent a potential therapeutic strategy to improve the efficacy of iRFA and prevent tumor recurrence.
