Insulin-like growth factor binding protein-6 (IGFBP-6) is induced by progesterone in breast cancer cells and regulates progesterone receptor (PR) via negative feedback. To further understand the mechanisms by which IGFBP-6 regulates PR and downstream signaling, proteomic analysis was performed in progesterone-treated T47D breast cancer cells following siRNA-mediated knockdown of IGFBP-6. Of the 8638 unique proteins identified, 29 proteins were downregulated, and 14 proteins were upregulated by progesterone treatment after IGFBP-6 knockdown. The decreased proteins were mostly identified as regulators of G2/M phase of the cell cycle. SH2D4A is induced by progesterone only when IGFBP-6 was high. To understand the role of SH2D4A in progesterone-induced signaling, SH2D4A was knocked down using siRNA prior to progesterone treatment. Knockdown of IGFBP-6 or SH2D4A leads to cell cycle arrest in G1, and both SH2D4A and IGFBP-6 regulate cyclin B. Treatment of cells with abemaciclib and nocodazole caused cell cycle arrest in G1 and G2/M, respectively, and decreased IGFBP-6, suggesting that IGFBP-6 is regulated in a cell cycle-dependent manner. These results identify a pathway linking progesterone to IGFBP-6 and SH2D4A, and to cell cycle progression in breast cancer cells.

Interleukin 32 (IL32) has context-dependent roles in carcinogenesis across cancer types. In this study, we examined IL32 in mesotheliomas.

IL32 protein expression was evaluated by immunohistochemistry in 56 mesothelioma tissue microarray specimens and by immunoblot analysis in cultured mesothelioma cell lines. The functional roles of IL32 were examined through ectopic expression of IL32β and IL32θ isoforms in D-Meso-Sonobe cells with epithelial-mesenchymal plasticity and through siRNA-mediated IL32 downregulation followed by cell-detachment-induced apoptosis assays in epithelioid mesothelioma cells.

IL32 immunoreactivity was detected in 20 of 56 mesothelioma tissue specimens, including cytoplasmic staining in 20 of 39 epithelioid cases, whereas little or no immunoreactivity was found in 17 sarcomatoid cases. In immunoblot analysis, an IL32 protein band was detected in two cultured epithelioid mesothelioma cell lines (MPM-2 and TCC-Meso-1), but not in sarcomatoid MPM-1 cells. Two IL32 isoforms, IL32β and IL32θ cDNAs, were isolated from MPM-2 cells. Ectopic expression of IL32θ, but not IL32β, inhibited the morphological transition from epithelioid to sarcomatoid features in D-Meso-Sonobe mesothelioma cells with mesothelial-mesenchymal transition plasticity. Conversely, siRNA-mediated downregulation of IL32 increased cell detachment-induced apoptosis in MPM-2 and TCC-Meso-1 epithelioid mesothelioma cells. Moreover, IL32 suppressed expression of secreted protein acidic and rich in cysteine, which is an epithelial-mesenchymal transition-related protein in mesothelioma cells.

These findings indicate that IL32 is expressed in epithelioid mesothelioma and may contribute to mesotheliomagenesis.

Neuropeptide Y [NPY; encoded by the NPY gene] is a widely expressed 36-amino-acid neuropeptide that regulates neuronal function, vascular regulation, and immune regulation; its role in glioblastoma [GBM] remains incompletely characterized. We performed an integrative in silico multi-scale transcriptomic analysis combining bulk RNA-sequencing of IDH-wildtype GBM [n = 169] and lower-grade glioma [n = 510] surgical resections from TCGA, normal cortical tissue from GTEx [n = 207], and four independent GEO validation cohorts of surgical GBM and non-tumor brain specimens [GSE4290, GSE50161, GSE131928 scRNA-seq of ~20,426 cells from 28 patients, and GSE194329 10X Visium spatial transcriptomics from five patients], along with survival modeling, pathway enrichment, single-cell RNA sequencing, spatial transcriptomics, and cell-cell communication analysis. NPY and its principal receptor, NPY1R, were significantly downregulated in GBM, while genes associated with hypoxia, angiogenesis, invasion, and immune suppression were upregulated. Single-cell analysis showed that NPY-axis transcript expression was elevated in neural progenitor-like populations. In contrast, hypoxia and metabolic programs were concentrated in mesenchymal tumors and stromal compartments, indicating distinct cellular contexts. Spatial analysis revealed a weak and heterogeneous relationship between NPY and hypoxia signatures, with substantial inter-patient variability and no significant global spatial cross-correlation. These findings indicate that loss of NPY signaling is a consistent feature of GBM and is associated with hypoxia-driven tumor states, while the spatial relationship between NPY and hypoxia appears weak, heterogeneous, and patient-specific.

Chronic inflammation is a hallmark of the breast cancer tumor microenvironment and is also known to be associated with disease progression and therapeutic response. Interleukin-1 (IL-1) signaling has been widely studied in breast cancer biology; however, the long-term effect of sustained IL-1 exposure on hormone receptor-positive breast cancer cells remain poorly understood. In this study, we investigated how chronic IL-1 exposure influences inflammatory response, hormone dependency, and therapeutic sensitivity in ERα+/PR+ breast cancer models, MCF7 and T47D. Chronic IL-1 exposure attenuated response to subsequent acute IL-1 treatment, but the chronically exposed cells remained sensitive to serum deprivation, retained dependence on estrogen or progesterone receptor signaling, and responded robustly to endocrine and chemotherapeutic treatments. Extensive changes in basal gene expression and histone modification revealed that chronic IL-1 exposure alters transcriptional reprogramming and chromatin remodeling. Together, these findings demonstrate that chronic IL-1 signaling drives selective inflammatory response in hormone receptor-positive MCF7 and T47D breast cancer cells. This work underscores the continued therapeutic relevance of hormone receptor-targeted strategies in chronically inflamed tumors and provides insight into how sustained inflammatory stress shapes tumor behavior and gene regulation predicted to promote tumor progression.

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil-circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast-osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1-CXCR4/CXCL12, PR3-RAGE, and DKK1-CKAP4-STAT6-CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC-neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is the major form of resistance to androgen receptor signaling inhibitors (ARSI) in advanced prostate cancer, characterized by pronounced invasiveness and lineage plasticity. Through in-depth analysis of prostate cancer cohorts, we found that glutamate ionotropic receptor kainate (GRIK) family members, specifically GRIK2 and GRIK5, are highly expressed in neural lineage plastic prostate cancer cells, NEPC patient-derived xenografts (PDX), and NEPC patient samples. Their expression positively correlates with neuroendocrine markers and inversely correlates with androgen receptor (AR) activity. Additionally, functional analyses indicated that AR has a direct transcriptional inhibitory effect on GRIK2 and GRIK5, and the absence of AR signaling leads to the upregulation of GRIK2 and GRIK5. Further RNA sequencing analysis revealed that GRIK5 silencing reprograms the cellular transcriptome, resulting in significant downregulation of AR signaling and fatty acid metabolism, while simultaneously activating immune and inflammatory responses in enzalutamide-resistant prostate cancer cells. In both cell line and NEPC PDX organoid models, loss of GRIK5 impaired proliferation and clonogenic growth. Notably, GRIK5 also contributes to enzalutamide resistance. Pharmacological evaluation revealed that Pan-GRIK antagonists exhibit anti-tumor activity, although the required relatively high concentrations suggest that more potent therapeutic strategies should be developed. Collectively, this study establishes that GRIK family members play critical roles in enzalutamide resistance and NEPC progression, highlighting GRIK signaling as a potential therapeutic target for overcoming lineage plasticity in prostate cancer.

Hepatocellular carcinoma (HCC) remains a malignancy with poor prognosis and limited therapeutic targets. Emerging evidence suggests a critical role for iron metabolism and ferroptosis in tumor progression. However, the involvement of hematopoietic lineage cell-specific protein 1 (HAX1) in HCC, particularly its regulatory role in ferroptosis, remains largely unknown. Here, we report that HAX1 is significantly upregulated in HCC tissues and correlates with advanced pathological stages and poor patient survival, suggesting its potential as an oncogene. Functionally, HAX1 overexpression promotes the proliferation and migration of HCC cells, while its knockdown inhibits these malignant phenotypes. Mechanistically, we demonstrate that HAX1 acts as a negative regulator of ferroptosis. Silencing HAX1 sensitizes HCC cells to the ferroptosis inducer IKE, leading to abnormal accumulation of intracellular ferrous iron (Fe²⁺) and increased lipid reactive oxygen species (ROS). Conversely, HAX1 overexpression suppresses iron overload and lipid peroxidation. Furthermore, we reveal that HAX1 maintains redox homeostasis by regulating the GSH/GPX4 antioxidant pathway. Knockdown of HAX1 depletes reduced glutathione (GSH), reduces glutathione peroxidase activity, and downregulates key ferroptosis defense proteins, including GPX4, FSP1, and SLC7A11. Our findings identify HAX1 as a critical promoter of HCC progression that functions by inhibiting ferroptosis through the modulation of iron homeostasis and the GSH/GPX4 pathway. Targeting the HAX1-mediated anti-ferroptotic mechanism may represent a promising therapeutic strategy for HCC treatment.

Chromosomal instability (CIN) arising from mitotic errors is a hallmark of cancer progression, yet how specific spindle assembly factors are co-opted to support aggressive tumor phenotypes remains incompletely understood. Hepatoma Upregulated Protein (HURP/DLGAP5), a Ran-regulated microtubule-associated protein essential for kinetochore fiber stabilization and chromosome congression, is frequently overexpressed in aggressive cancers. Here, we investigated HURP's role across a breast cancer metastatic gradient-immortalized MCF10A, the low-metastatic luminal T47D, and the highly metastatic triple-negative MDA-MB-231 cell lines-integrating quantitative spindle analysis, kinetochore tension measurements, spindle checkpoint profiling, migration dynamics, and three-dimensional spheroid modeling. We show that total HURP protein levels increase with metastatic potential, yet spindle-bound HURP is paradoxically reduced in MDA-MB-231 cells, indicating cytoplasmic mislocalization despite increased total protein levels. HURP silencing induced cell-line-specific defects: moderate disorganization and misorientation in MCF10A and T47D cells, but catastrophic spindle collapse, apoptosis, and G2/M arrest in MDA-MB-231 cells. Mechanistically, HURP depletion disrupted the spindle-associated levels and distributions of TPX2, Aurora-A, and NuMA in a subtype-dependent manner, implicating HURP as a context-dependent stabilizer of this mitotic regulatory axis. HURP loss reduced interkinetochore tension in all cell lines, but only MCF10A and T47D cells mounted a proportional BubR1-dependent checkpoint response; MDA-MB-231 cells showed reduced checkpoint signaling, consistent with constitutive spindle assembly checkpoint (SAC) attenuation in triple-negative breast cancer. Beyond mitosis, HURP depletion impaired collective migration and converted MDA-MB-231 cells from super-diffusive, amoeboid-like motility to sub-diffusive behavior, while minimally affecting the less aggressive cell lines. HURP-depleted MDA-MB-231 spheroids were significantly larger, less compact, and less spherical than controls, linking spindle regulation to tissue-level architectural coherence. These findings establish HURP as a multifunctional regulator coordinating mitotic fidelity, migration plasticity, and tumor architecture in breast cancer, with a selective dependency in highly metastatic cells, positioning it as a promising therapeutic target for aggressive breast cancers.

Potassium (K⁺) channels have been frequently linked to cancer progression; however, their contribution varies across tumour types and experimental models. This heterogeneity indicates that gene-level characteristics such as expression, co-expression, or mutational status are inadequate for explaining channel involvement in oncogenic signalling. Here, we performed a cross-study comparison of experimentally validated K⁺ channel interactomes, we show that K⁺ channel regulation is highly context-dependent and does not exhibit conserved pan-cancer signatures. By directly comparing proximity-labeling and affinity-purification datasets across different K⁺ channel families, we identify a limited number of recurrent organizational architectures rather than universal signalling modules. KCa3.1 (encoded by KCNN4), Kir2.1 (KCNJ2), and TASK-1 (KCNK3) assemble signalling-permissive interactomes integrating adhesion complexes, junctional scaffolds, vesicular trafficking pathways, and receptor-associated signalling nodes. In contrast, Kv11.1 (encoded by KCNH2) displays an interactome predominantly enriched for proteostasis and endoplasmic reticulum-associated components, indicating a proteostasis-centered organizational profile with comparatively limited signalling integration. Kv1.3 (encoded by KCNA3), instead, consistently associates with mitochondrial and metabolism-linked proteins and functionally connects metabolic state to downstream transcriptional regulators, rather than regulating its own transcription. Higher-order intersection and pathway-specific analyses indicate that functional convergence across the above channels emerges from shared architectural principles rather than extensive molecular overlap. In conclusion, this study identifies interactome architecture as a central organizational level for understanding K⁺ channel function in cancer. The integration of pan-cancer gene-level analyses with systematic comparison of interaction architectures offers a coherent framework for interpreting the functional heterogeneity observed across channels, families, and tumor contexts. This perspective suggests that therapeutic strategies may benefit from targeting channel-centered network architectures rather than isolated channels alone, highlighting ion channels as structural components of broader signalling systems rather than solely bioelectrical regulators.

Cervical cancer is a malignant disease that affects women worldwide and is associated with both high incidence and a high mortality rate. miR-34 is a direct transcriptional-target of p53 and is downregulated in several types of cancers. 1,4-Naphthoquinones (NQs) have anticancer properties and have been used to modulate miR-34 expression. We tested (3-chloro-NQ-2-yl)-alanine (ANQCl), -methionine (MNQCl), -glycine (GNQCl), -phenylalanine (FNQCl), -asparagine (NNQCl), and (1,4-napthoquinon-2-yl)-asparagine (NNQ) in immortal and tumorigenic cells, both HPV-positive and -negative, simulating precancerous and cancerous status to observe the response of the p53-miR-34 system, migration and invasion. A dose-response was achieved to determine the IC50 of the compounds in SiHa, CaLo, C33-A and HaCaT cells. HaCaT cell migration inhibition was more potent than in SiHa, CaLo, and C33-A cells, while invasion hindrance was more evident in the tumorigenic SiHa, CaLo and C33-A. NNQCl, GNQCl, ANQCl and FNQCl compounds induced p53 overexpression in SiHa and CaLo cells. Compound ANQCl in SiHa and FNQCl in CaLo induced miR-34a overexpression, probably via p53. Migration and invasion of most compounds decreased independently of p53-miR-34. NQ-amino acids exert effect on cell proliferation, migration and invasion in cervical cancer cells, suggesting their potential use in the field of cancer treatment.