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PubMed2025

Beta-catenin/sirtuin 1/farnesoid X receptor pathway promotion of portal vein ligation and parenchymal transection-induced rapid liver regeneration.

BACKGROUND: By accelerating the regeneration of the future liver remnant, portal vein ligation and parenchymal transection allows for more extensive hepatectomy. Given that the mechanism remains poorly understood, the aim of this study was to investigate the mechanism of portal vein ligation and parenchymal transection-induced liver regeneration. METHODS: A portal vein ligation and parenchymal transection-induced liver regeneration mouse model was established, followed by RNA microarray analysis to identify candidate molecules. Genomic deletion and chemical manipulation of target molecules were used to explore their functions in portal vein ligation and parenchymal transection-induced liver regeneration. Validation was conducted using a diseased liver model and human samples. RESULTS: Portal vein ligation and parenchymal transection-induced liver regeneration was significantly accelerated compared with that in sham-operated mice (P < .05). An RNA microarray revealed that Sirtuin 1 is a crucial molecule in the proliferation of the future liver remnant. Regardless of whether Sirtuin 1 is inhibited chemically or through genetic deletion, portal vein ligation and parenchymal transection-induced liver regeneration is distinctly attenuated. Further investigation revealed that Sirtuin 1 promoted portal vein ligation and parenchymal transection-induced liver regeneration via the farnesoid X receptor. In addition, beta-catenin also was found to participate in the process of future liver remnant proliferation. Chemical inhibition of beta-catenin markedly impaired but activation of WNT/beta-catenin mildly enhanced portal vein ligation and parenchymal transection-induced liver regeneration (P < .05). Deletion of Sirtuin 1 blocked the facilitating effect of beta-catenin on portal vein ligation and parenchymal transection-induced liver regeneration. These findings were validated in diseased liver models and patient samples, confirming the correlation between the beta-catenin/Sirtuin 1/farnesoid X receptor pathway and portal vein ligation and parenchymal transection-induced liver regeneration. CONCLUSION: Activation of the beta-catenin/Sirtuin 1/farnesoid X receptor pathway offers critical mechanistic insights into accelerating portal vein ligation and parenchymal transection-induced liver regeneration. Modulation of beta-catenin/Sirtuin 1/farnesoid X receptor may therefore improve clinical outcomes in patients receiving staged hepatectomy.

Liver Regeneration↗

PubMed2026

Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions.

Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3'untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation.

MicroRNAs↗

PubMed2001

Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release.

The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.

Adenocarcinoma↗

PubMed2026

AGRN activates GPX4 via the Wnt/beta-catenin signaling pathway to suppress ferroptosis in cervical cancer cells.

Cervical cancer remains a leading cause of cancer-related deaths among women worldwide. Targeting ferroptosis, a regulated form of cell death driven by lipid peroxidation, has emerged as a promising therapeutic strategy. This study aimed to elucidate the mechanisms by which cervical cancer cells acquire resistance to ferroptosis. AGRN expression and its prognostic significance were analyzed in cervical cancer using TCGA and GTEx data. In vitro, AGRN levels were measured in HeLa, CaSki, and Ect1/E6E7 cells via qRT-PCR. mRNA and protein expression levels of AGRN, beta-catenin, and ferroptosis-related markers were evaluated by qRT-PCR and western blot (WB). Cell viability, RSL3 sensitivity (IC50), and lipid ROS were assessed via CCK-8 assay and flow cytometry. In a xenograft model, RSL3's effect on tumor growth was examined. Immunohistochemistry (IHC) and molecular analyses (qRT-PCR, WB, and flow cytometry) were performed on tumor tissues to evaluate AGRN, beta-catenin, Ki-67, ferroptosis-related genes, and lipid ROS. It is found through research that, AGRN was significantly upregulated in cervical cancer tissues and cell lines. Its overexpression activated Wnt/beta-catenin signaling, resulting in elevated GPX4 and SLC7A11 levels and reduced CHAC1 and PTGS2 expression levels. These alterations decreased lipid ROS accumulation and enhanced resistance to RSL3-induced ferroptosis, an effect further confirmed in xenograft models. In short, In short, AGRN promotes ferroptosis resistance in cervical cancer by activating the Wnt/beta-catenin signaling pathway and upregulating GPX4 expression. Targeting the AGRN-Wnt/beta-catenin-GPX4 axis may represent a novel therapeutic approach for cervical cancer.

Humans↗

PubMed2025

Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas.

Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent CTNNB1 mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic, and epigenetic findings of 12 PS cases. The tumors affected 7 men and 5 women with a median age of 66 years and were located in the paraspinal/paravertebral region (n = 11) and the thigh (n = 1). Median tumor size was 82 mm (range, 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid-to-ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), desmin (2/6), and androgen receptor (1/4). Pankeratin (AE1/AE3), progesterone receptor, synaptophysin, chromogranin, and INSM1 were negative. All tested cases harbored CTNNB1 mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (gene ontology - biological process [GO-BP]). Additionally, upregulated genes were related to various fetal cell types from the cell type signature data set (MSigDB), particularly of neuronal and epithelial lineage. Immunohistochemical assessment of potential markers identified through gene expression analysis revealed focal-to-diffuse expression of GLUT1 (6/6) and focal/multifocal expression of Brachyury (4/9) and HuD (3/7). Follow-up information, available for 10 cases (median duration of 18 months; range, 7-69 months), showed local recurrences and metastatic spread in 2 patients each. Evidence of response to radiotherapy was documented in one tumor. Altogether, this study expands knowledge on PS and suggests biological links with SPNP, including a potential shared cell of origin.

Humans↗

PubMed2025

Single-cell spatial mapping reveals alteration of tissue microenvironment during early colorectal cancer.

Familial adenomatous polyposis (FAP) is a rare, hereditary syndrome that raises the risk of developing colorectal cancer (CRC). This disease model is well suited for studying the early stages of malignant transformation. Our spatial CODEX experiments reveal that, in contrast to normal mucosa, FAP mucosa, pre-cancer polyps and colorectal cancers exhibit substantial alterations in the cell type composition and tissue microenvironment. These early alterations include: an increase in the population of cancer-associated fibroblasts (CAFs), and the inhibition of tumor infiltrated lymphocytes and cell-adhesion protein by CAFs, the transformation of memory T cells into regulatory T cells, nuclear translocation of beta-catenin from the cell membrane, a decrease in the M1:M2 macrophage ratio, a notable increase in angiogenesis events. Our studies define the early stem cell, stromal, and immune steps of colorectal cancer and may benefit early detection, and therapeutic intervention.

Co-detection by Indexing (CODEX)↗

PubMed2026

Oncogene activation mechanism determines the limits of targeted protein degradation.

Protein degrader drugs such as PROTACs are being advanced as therapeutics targeted against oncogenic proteins. During tumorigenesis, oncogenic proteins can become constitutively activated via mechanisms including gene amplification, which increases protein production, and point mutations, which can extend protein half-life. Few experimental studies have addressed how disease-associated changes in target protein homeostasis influence PROTAC activity. We developed orthogonal methods to increase production or enhance stability of β-catenin, an important oncoprotein and target for degrader therapeutics, and used the dTAG system to evaluate the consequences for PROTAC activity. Stabilizing oncogenic missense mutations increase protein expression up to 5-fold but do not alter the PROTAC-imposed minimal steady-state level. In contrast, transcriptional upregulation increases both pre- and post-treatment target levels, revealing a synthesis-dependent ceiling on achievable depletion. Our results highlight distinct constraints on PROTAC activity arising from different mechanisms of oncogene activation, with potential implications for preclinical modeling, drug resistance and personalized medicine.

Humans↗

PubMed2026

A novel 2D and 3D model for primary adrenocortical carcinoma of advanced and metastasized stage co-secreting cortisol, aldosterone, testosterone, 18-oxocortisol and 18-hydroxycortisol.

Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with poor survival rates and few treatment options. Preclinical models are indispensable to further strengthen our understanding of disease progression and development of novel therapeutic treatments. Here, we report the establishment of a new cell line named ZUC-1 originating from the resection of an advanced primary ACC and its characterization at the genomic, cellular and molecular level. ZUC-1 cells were successfully propagated as monolayer cultures and three-dimensional spheroids. LC-MS/MS analysis revealed for ZUC-1 cells co-secretion of cortisol, aldosterone and testosterone, and the model represented in direct comparison with other current ACC pre-clinical models furthermore significantly elevated expression of SF-1, CYP11B1 and CYP11B2 genes. Whole genome sequencing identified various mutations in genes linked to DNA repair/stress response, stemness, and also steroidogenesis. Interestingly, ZUC-1 represents genotypic and phenotypic variations that might be of interest beyond ACC, including congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS). Moreover, 18-oxocortisol and 18-hydroxycortisol release was detected in ZUC-1, conditions which are often linked to hyperaldosteronism, but forskolin, potassium and, at higher concentration, angiotensin II modulability of CYP11B2 for this model is retained. ZUC-1 spheroids exhibited furthermore an intra-spheroidal heterogeneous mix of canonical and non-canonical Wnt pathway activation. We conclude that due to its origin and unique geno- and phenotypes, ZUC-1 represents an intriguing model to further gain a basic understanding of adrenal function, the pathogenesis of ACC, but it might be also of interest in the context of CAH and PCOS.

Humans↗