Role of the ETV5/p38 signaling axis in aggressive thyroid cancer cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic (ATC) face a much poorer prognosis than those cancers. Around 25% of PDTCs 35% ATCs carry the BRAF V600E mutation, which constitutively activates MAPK pathway, key driver cell growth. Although combining MEK inhibitors can shrink tumors, resistance often develops. The exact cause this remains unclear. We previously found that in PDTC ATC cells mutation is strongly linked to expression ETV5, transcription factor downstream pathway. In current study, we observed significant association between ETV5 activation p38, central component MAPK14 Upon reduction levels, p38 decreased, along its upstream regulators MKK3/MKK6. This suggests p38/MAPK14 pathways are interconnected has oncogenic properties these Using high-throughput screening, established inhibitor dabrafenib showed strong synergy vitro , including resistant trametinib had acquired secondary TP53 mutation. then tested combination genetically engineered mouse model (GEMM) ATC. Overall, our findings suggest an link pathway dabrafenib-targeted therapy could improve treatment outcomes for aggressive However, more specific effective required fully harness potential.

Language: Английский

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Antibody-Targeted Bismuth Gadolinium Nanoconjugate for Image-Guided Radiotherapy of Hepatocellular Carcinoma

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Hepatocellular carcinoma (HCC), one of the most lethal cancers liver, has limited treatment options at advanced stages. Here, bismuth gadolinium (BiGd) nanoparticles (NPs) conjugated with anti-vascular endothelial growth factor antibody (aVEGF) are designed and tested for targeted image-guided radiation therapy against HCC. The BiGd NPs synthesized using sol-gel technique, functionalized silica NPs, labeled fluorescent protamine-rhodamine B. For tumor targeting, aVEGF, an in vitro study confirms binding aVEGF-BiGd nanoconjugate to McA-RH7777 hepatoma cells. Biocompatibility is evaluated cells, no cytotoxicity observed even 250 μg/mL. Also, demonstrates vivo microcomputed tomography contrast enhancement. and/or (RT) conducted female BALB/c nude mice subcutaneously implanted a significant reduction size treated RT compared other groups (p < 0.01). combined effect exhibits decreased vascularity, cell proliferation, increased apoptosis. This potential developed hybrid radiotherapy

Language: Английский

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Liver cancer: Current status of preclinical research

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 34

Published: Jan. 1, 2025

Language: Английский

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Protective role of hesperetin in sorafenib-induced hepato- and neurotoxicity in mice via modulating apoptotic pathways and mitochondrial reprogramming

Life Sciences, Journal Year: 2023, Volume and Issue: 336, P. 122295 - 122295

Published: Nov. 23, 2023

Language: Английский

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Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives

Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 3, 2024

Abstract Liver cancer is the sixth most commonly diagnosed and third leading cause of death in world, hepatocellular carcinoma (HCC) common form liver cancer. More than half HCC patients are at an advanced stage often require systemic therapy. Dysregulation activity receptor tyrosine kinases (RTKs) involved development progress HCC, RTKs therefore potential targets for therapy (aHCC). Currently, a total six small molecule kinase inhibitors (TKIs) have been approved aHCC, including first-line sorafenib, lenvatinib, donafenib, second-line regorafenib, cabozantinib, apatinib. These TKIs improved survival, which associated with disease stage, etiology, function, tumor burden, baseline levels alpha-fetoprotein, treatment history. This review focuses on clinical outcomes these key trials, retrospective real-world studies discusses future perspectives aim to provide up-to-date evidence decision-making aHCC.

Language: Английский

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Low miR-936-mediated upregulation of Pim-3 drives sorafenib resistance in liver cancer through ferroptosis inhibition by activating the ANKRD18A/Src/NRF2 pathway

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Oct. 24, 2024

Objective Sorafenib, a multikinase inhibitor, is currently the standard treatment for advanced liver cancer. However, its application has become limited by development of drug resistance. We intended to explore mechanisms underlying sorafenib resistance, therefore identifying an effective strategy overcome resistance remain challenges. Methods Here, follow-up cancer patients undergoing therapy, as well animal tumor challenge and were performed. The sorafenib-resistant cell lines Huh7/SOR HepG2/SOR also established. miRNA mRNA microarray analyses, TargetScan prediction, dual luciferase reporter assay, RNA pull-down co-mmunoprecipitation (Co-IP) assays, transcription factor-specific NRF2 iron detection lipid peroxidation quantification ROS measurement GSH/GSSG GSH-px quantitative assays used. Results showed that upregulation provirus-integrating site Moloney murine leukemia virus 3 (Pim-3) predicted poor response unsatisfactory prognosis in sorafenib-treated patients. Similarly, Pim-3 expression was positively associated with cells. Furthermore, microRNA-936 (miR-936) targeted 3’-noncoding region (3'-UTR) but exhibited lower cells than their parental high mediated miR-936 insufficiency activated ANKRD18A/Src/NRF2 pathway which rearranged indicated markers involved distribution homeostasis. MiR-936 overexpression GV102-Pim-3-shRNA significantly attenuated activity decrease Ankyrin repeat domain-containing protein 18A (ANKRD18A), Src, Nuclear factor (erythroid-derived 2)-like 2 (NRF2), especially decreasing nuclear retention transcriptional activity. prompted ferroptosis because transfection mimics, GV102-NRF2-shRNA plasmid increased transferrin receptor 1 (TFR1) divalent metal transporter (DMT1) decreased solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1), thus facilitating accumulation intracellular Fe 2+ , peroxides, reactive oxygen species (ROS) reducing (GSH) level. Moreover, elevated Pim-3, resulting from absence enhances inhibiting ferroptosis. Conclusion can be regarded target

Language: Английский

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Adhesion G Protein-Coupled Receptor G2 Promotes Hepatocellular Carcinoma Progression and Serves as a Neutrophil-Related Prognostic Biomarker

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16986 - 16986

Published: Nov. 30, 2023

Adhesion G protein-coupled receptor G2 (ADGRG2) is an orphan adhesion (GPCR), which performs a tumor-promoting role in certain cancers; however, it has not been systematically investigated hepatocellular carcinoma (HCC). In the current study, we utilized multiple databases to analyze expression and diagnostic prognostic value of ADGRG2 HCC its correlation with immune infiltration inflammatory factors. The function upstream regulatory miRNA were validated through qPCR, Western blot, CCK8, wound healing, dual luciferase assays. It turned out that was significantly higher had poor survival rate, especially AFP ≤ 400 ng/mL subgroups. Functional enrichment analysis suggested may be involved cancer pathways immune-related pathways. vitro, siRNA-mediated silencing could inhibit proliferation migration Huh7 HepG2 cells. There highly significant positive between neutrophils. Moreover, NET-related genes filtered confirmed, such as ENO1 S100A9. Meanwhile, high also accompanied by highest number cytokines, chemokines, chemokine receptors good immunotherapy efficacy. Finally, AGDGR2 sensitive two drugs (PIK-93 NPK76-II-72-1) can targeted miR-326. conclusion, serve novel biomarker drug target for diagnosis, immunotherapy, prognosis related neutrophils process liver development.

Language: Английский

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Three Types of Isocoumarins with Unusual Carbon Skeletons from Artemisia dubia var. subdigitata and Their Antihepatoma Activity

Chinese Journal of Chemistry, Journal Year: 2024, Volume and Issue: 42(16), P. 1901 - 1912

Published: April 17, 2024

Comprehensive Summary Ten novel isocoumarins, including four pairs of enantiomers, were isolated from Artemisia dubia var. subdigitata (Asteraceae) . Compounds 1 , 2 and 3a / 3b possessed a unique 6/6/6‐tricyclic system comprising an unusual 1‐(2‐methylcyclohexyl) propan‐1‐one moiety fused with isocoumarin core skeleton. 4a 4b characterized as unexpected 2,5‐dimethylcyclohexan‐1‐one scaffold, compounds 5a 5b 6a 6b rare 1,2‐ seco ‐isocoumarin. Their structures absolute configurations elucidated through spectroscopic data, X‐ray crystallography, ECD NMR calculations DP4+ analyses. Plausible biosynthetic pathways proposed the naturally occurring isocoumarin. Network pharmacological analysis suggested that targets compound significantly enriched in cell cycle PI3K‐Akt signaling pathway. The molecular docking revealed had high binding affinity CDK2 (total score: 6.8717). Furthermore, exhibited inhibitory activity on three human hepatoma lines, ratios 85.1% 84.5% (HepG2), 88.2% 87.3% (Huh7), 69.2% 69.1% (SK‐Hep‐1) at 200 μmol·L –1 respectively.

Language: Английский

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EGFR bypass activation mediates acquired resistance to regorafenib in hepatocellular carcinoma

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Nov. 13, 2024

Background Regorafenib, a tyrosine kinase inhibitor (TKI), is used in the treatment of unresectable hepatocellular carcinoma (HCC). However, occurrence acquired resistance limits its antitumor efficacy. While multiple studies have highlighted crucial role bypass activation TKI resistance, few focused on regorafenib HCC. Methods High-throughput proteomics was to identify differential proteins associated with between regorafenib-resistant cells and parental cells. The ability epidermal growth factor receptor (EGFR) inhibition reverse evaluated both vitro vivo using direct microscopic observation, CCK-8 assay, colony formation Annexin V-FITC/propidium iodide double staining, cell cycle analysis, western blotting, xenograft model. Results expression EGFR, member (RTK) family, significantly increased HCC compared Pharmacological EGFR gefitinib restored sensitivity regorafenib. In mouse model, sensitized resistant tumors Additionally, levels RAS, RAF, P-ERK1/2, components downstream signaling pathway, were positively expression. Conclusion overexpression promotes through RAS/RAF/ERK Inhibition restores regorafenib, combination demonstrates significant efficacy . These findings suggest that this could be potential strategy for patients advanced

Language: Английский

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The Combination Sorafenib-raloxifene-loratadine as a Novel Potential Therapeutic Approach Against Human Liver Cancer

In Vivo, Journal Year: 2023, Volume and Issue: 37(3), P. 1156 - 1163

Published: Jan. 1, 2023

Background/Aim: Liver cancer is one of the malignancies with highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve response patients to in several cancers. The aim present study was merge these two strategies evaluate whether two-drug- or three-drug- combination sorafenib, raloxifene, loratadine improves antineoplastic effect on human liver cells comparison single-drug effect. Materials Methods: cell lines HepG2 HuH7 were studied. metabolic activity determined using MTT assay. inhibitory concentrations (IC₂₀ IC₅₀) calculated from results used drug-combination experiments. Apoptosis survival studied by flow cytometry colony formation assay, respectively. Results: In both lines, two-drug three-drug combinations significantly reduced increased percentage apoptotic compared addition, all colony-forming capacity line. Surprisingly, raloxifene apoptosis similar that observed combinations. Conclusion: triple sorafenib-raloxifene-loratadine may be a promising approach treatment patients.

Language: Английский

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