ArticleBMC medicine2023
ACVRL1 drives resistance to multitarget tyrosine kinase inhibitors in colorectal cancer by promoting USP15-mediated GPX2 stabilization.
Article in BMC medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Rewiring redox defense: Nrf2-driven antioxidant signaling as a gateway to programmed cell death activation in colorectal cancer.Genes & diseases · 2027Review
- Targeting USP8 with odoroside A regulates LXRβ-mediated fatty acid metabolic reprogramming against colorectal cancer.Acta pharmacologica Sinica · 2026Article
- Multi-omics Analysis Reveals the Prognostic and Therapeutic Value of TGF-β Signaling-related Genes in Idiopathic Pulmonary Fibrosis.Biochemical genetics · 2026Article
- miR-141-5p positively regulates ACVRL1 expression to promote cervical cancer progression.Human cell · 2026Article
- USP10 confers lenvatinib resistance in hepatocellular carcinoma by deubiquitinating the GPX2.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Identification of key genes as diagnostic biomarkers for lung adenocarcinoma using bioinformatics and machine learning.Discover oncology · 2026Article
- Unraveling regorafenib resistance: metabolic reprogramming, tumor plasticity, and novel approaches to overcome therapy failure.Archives of pharmacal research · 2026Review
- Integrative genomic and immune landscape analysis of intimal sarcomas for emerging therapeutic targets and immunotherapy strategies.Frontiers in immunology · 2026Article
- Ubiquitin-specific proteases as key regulators in the malignant progression and therapy resistance of colorectal cancer: current insights and future perspectives.Discover oncology · 2025Review
- USP15 Facilitates Colorectal Cancer Immune Evasion through SMYD3/CCL2-Dependent Myeloid-Derived Suppressor Cell Recruitment.Cancer immunology research · 2025Article
- CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis.Oncogene · 2025Article
- Article
- Prognostic Value of Ferroptosis-Immunity-Related Signature Genes in Cervical Cancer Radiotherapy Resistance and Risk Modeling.Cancer management and research · 2025Article
- NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma.Oncogenesis · 2024Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMultitarget tyrosine kinase inhibitors (mTKIs) such as Regorafenib and Sorafenib have already been approved for the treatment of many solid tumours. However, the efficacy of mTKIs in colorectal cancer (CRC) is limited; the underlined mechanism remains largely elusive. Our study was aimed to find out the resistance mechanism of mTKIs in CRC.
methodsRNA sequencing was used to identify the expression of Activin A receptor-like type 1 (ACVRL1) under the treatment of mTKIs. Gain/loss-of-function experiments were performed to assess the biological function of ACVRL1 in resistance to mTKIs. The underlying mechanisms of ACVRL1-mediated mTKI resistance were investigated by using liquid chromatography-mass spectrometry assays (LC-MS), co-immunoprecipitation assays (Co-IP), chromatin immunoprecipitation assays, ubiquitination assays, dual luciferase reporter assays, etc.
resultsRNA sequencing identified the activation of ACVRL1 under the treatment of mTKIs in CRC cells. ACVRL1 knockdown and overexpression significantly affects the sensitivity of CRC cells to mTKIs both in vitro and vivo. Mechanistically, we found the β-catenin/TCF-1-KCNQ1OT1/miR-7-5p axis mediated the activation of ACVRL1. Furthermore, LC-MS assays indicated the interaction between ACVRL1 and glutathione peroxidase 2(GPX2) protein. IP assay defined ACVRL1 truncation (282-503aa) could be responsible for interacting with GPX2, and rescue experiments with ACVRL1 truncations confirmed the importance of this interaction in driving mTKI resistance. Co-IP assays confirmed that ACVRL1 associates with ubiquitin-specific peptidase 15(USP15) which directly deubiquinates GPX2 at the K187(K, lysine) site, leading to the accumulation of GPX2 protein. Rescue experiments performed with the lysine mutants in GPX2 CRISPR knockout cell model confirmed the importance of GPX2 K187 mutant. As a result, the increased ROS clearance and decreased cell apoptosis eventually lead to mTKI resistance in CRC.
conclusionsOur results demonstrate that the Wnt/β-catenin/KCNQ1OT1/miR-7-5p/ACVRL1/GPX2 biological axis plays a vital role in CRC, targeting which may be an effective approach for overcoming mTKI resistance.
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