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MicroRNA-142-3p Overcomes Drug Resistance in Hepatocellular Carcinoma by Targeting YES1 and TWF1.

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Τίτλος: MicroRNA-142-3p Overcomes Drug Resistance in Hepatocellular Carcinoma by Targeting YES1 and TWF1.
Συγγραφείς: Mahboobnia K; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia., Kabir TD; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia., Hou R; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia., Liu P; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia., Forrest A; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia., Beveridge DJ; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia., Richardson KL; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia., Stuart LM; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia., Yeoh GC; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia., Leedman PJ; Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, Perth, WA 6009, Australia.; Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia.
Πηγή: International journal of molecular sciences [Int J Mol Sci] 2025 Apr 27; Vol. 26 (9). Date of Electronic Publication: 2025 Apr 27.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Imprint Name(s): Original Publication: Basel, Switzerland : MDPI, [2000-
Ιατρικοί όροι (MeSH): MicroRNAs*/genetics , MicroRNAs*/metabolism , Carcinoma, Hepatocellular*/genetics , Carcinoma, Hepatocellular*/drug therapy , Carcinoma, Hepatocellular*/pathology , Carcinoma, Hepatocellular*/metabolism , Liver Neoplasms*/genetics , Liver Neoplasms*/drug therapy , Liver Neoplasms*/pathology , Liver Neoplasms*/metabolism , Drug Resistance, Neoplasm*/genetics , Proto-Oncogene Proteins c-yes*/genetics , Proto-Oncogene Proteins c-yes*/metabolism, Gene Expression Regulation, Neoplastic/drug effects ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Sorafenib/pharmacology ; Phenylurea Compounds/pharmacology ; Apoptosis/drug effects ; Apoptosis/genetics ; Quinolines/pharmacology ; Epithelial-Mesenchymal Transition/drug effects ; Epithelial-Mesenchymal Transition/genetics ; Cell Movement/drug effects ; Cell Movement/genetics ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction/drug effects ; Humans ; Cell Line, Tumor
Περίληψη: Resistance to tyrosine kinase inhibitors (TKIs, e.g., sorafenib and lenvatinib) presents a significant hurdle for hepatocellular carcinoma (HCC) treatment, underscoring the need to decipher the underlying mechanisms for improved therapeutic strategies. MicroRNAs (miRNAs) have emerged as critical modulators in HCC progression and TKI resistance. In this study, we report a positive correlation between the expression levels of a tumor suppressor miRNA, miR-142-3p, and increased sensitivity to sorafenib and lenvatinib, supported by clinical data from the BIOSTORM HCC cohort. Overexpression of miR-142-3p in TKI-resistant HCC cells significantly inhibited proliferation and colony formation, induced apoptosis, increased cell cycle arrest at the G2 phase, and reduced migration and invasion by reversing epithelial-mesenchymal transition. Notably, combining miR-142-3p with lenvatinib synergistically inhibited growth in both inherent and acquired TKI-resistant HCC cells by modulating critical signaling pathways, including STAT3, PI3K/AKT, MAPK, YAP1, and by impeding autophagic influx. RNA-sequencing of a TKI-resistant HCC cell line ± miR-142-3p overexpression identified YES1 and TWF1 as direct downstream target genes of miR-142-3p, both of which are key genes associated with drug resistance in HCC. Small interfering RNA (siRNA)-mediated knockdown of these genes mirrored the antitumor effects of miR-142-3p and enhanced TKI sensitivity, with YES1 knockdown decreasing YAP1 phosphorylation, and TWF1 knockdown inhibiting autophagy. Collectively, these findings indicate that restoring miR-142-3p expression or targeting its downstream effectors YES1 and TWF1 offers a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC.
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Contributed Indexing: Keywords: TWF1; YES1; drug resistance; hepatocellular carcinoma; miR-142-3p; tyrosine kinase inhibitors
Substance Nomenclature: 0 (MicroRNAs)
0 (MIRN142 microRNA, human)
EC 2.7.10.2 (Proto-Oncogene Proteins c-yes)
EC 2.7.10.2 (YES1 protein, human)
9ZOQ3TZI87 (Sorafenib)
0 (Phenylurea Compounds)
0 (Quinolines)
EE083865G2 (lenvatinib)
0 (Protein Kinase Inhibitors)
Entry Date(s): Date Created: 20250514 Date Completed: 20250514 Latest Revision: 20250516
Update Code: 20260130
PubMed Central ID: PMC12071648
DOI: 10.3390/ijms26094161
PMID: 40362400
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1422-0067
DOI:10.3390/ijms26094161