Biological effect of ETV4 and the underlying mechanism of its regulatory effect on epithelial‑mesenchymal transition in intrahepatic cholangiocarcinoma cells

Liu, Li; Feng, Yong; Xiang, Xuelian; Xu, Mengtao; Tang, Guodu

doi:10.3892/ol.2024.14479

Oncol Lett

2024

DOI: 10.3892/ol.2024.14479

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Biological effect of ETV4 and the underlying mechanism of its regulatory effect on epithelial‑mesenchymal transition in intrahepatic cholangiocarcinoma cells

Li Liu,

Yong Feng,

Xuelian Xiang

et al.

Abstract: Intrahepatic cholangiocarcinoma (ICC) is a highly invasive malignant tumor. The prognosis of patients with ICC after radical surgical resection remains poor, due to local infiltration, distant metastasis, a high recurrence rate and lack of effective treatment strategies. E26 transformation-specific sequence variant 4 (ETV4) is a pro-carcinogenic factor that is upregulated in several tumors; however, the role of ETV4 in ICC is relatively unknown.

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From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development

Lin,

Tsai,

Hsu

et al. 2024

Marine Drugs

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Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC50 values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-β-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE’s main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs.

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From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development

Lin,

Tsai,

Hsu

et al. 2024

Marine Drugs

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Elevated ETV4 expression in cholangiocarcinoma is linked to poor prognosis and may guide targeted therapies

Okpete,

Byeon

2024

World J Gastrointest Oncol

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Cholangiocarcinoma (CCA), a highly aggressive bile duct cancer, is associated with late-stage diagnosis and limited treatment options, leading to poor patient outcomes. Early detection and personalized treatment strategies are crucial. The study by Wang et al highlights the prognostic potential of the PEA3 subfamily genes (ETV1 , ETV4 , and ETV5 ) in CCA, identifying ETV4 as a particularly promising biomarker. Their bioinformatic analysis revealed that elevated ETV4 expression correlates with poorer survival, positioning it as a strong indicator of disease progression. These findings suggest that ETV4 could enhance prognostic precision and guide personalized therapies, although further validation through large-scale clinical trials is essential. Challenges in clinical application include the need for comprehensive experimental validation and addressing the tumor heterogeneity in CCA. Future research should focus on validating these biomarkers in diverse cohorts and developing targeted therapies, especially in regions where CCA is endemic.

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Biological effect of ETV4 and the underlying mechanism of its regulatory effect on epithelial‑mesenchymal transition in intrahepatic cholangiocarcinoma cells

Cited by 2 publications

References 50 publications

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development

Elevated ETV4 expression in cholangiocarcinoma is linked to poor prognosis and may guide targeted therapies

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