دورية أكاديمية
أعرض في EDS

KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway.

التفاصيل البيبلوغرافية
العنوان: KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway.
المؤلفون: Xu H; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Huo R; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Li H; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Jiao Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Weng J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Wang J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Yan Z; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Zhang J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Zhao S; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., He Q; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Sun Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Wang S; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China.; China National Clinical Research Center for Neurological Diseases, Beijing, China., Cao Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital medical university, Beijing, China caoyong@bjtth.org.; China National Clinical Research Center for Neurological Diseases, Beijing, China.; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
المصدر: Stroke and vascular neurology [Stroke Vasc Neurol] 2023 Jun; Vol. 8 (3), pp. 197-206. Date of Electronic Publication: 2022 Nov 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BMJ Country of Publication: England NLM ID: 101689996 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2059-8696 (Electronic) Linking ISSN: 20598688 NLM ISO Abbreviation: Stroke Vasc Neurol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BMJ, [2016]-
مواضيع طبية MeSH: Transforming Growth Factor beta*/metabolism , Intracranial Arteriovenous Malformations*/genetics, Humans ; Mice ; Animals ; Proto-Oncogene Proteins p21(ras)/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Human Umbilical Vein Endothelial Cells/metabolism ; Mutation ; Brain/metabolism ; Smad4 Protein/genetics ; Smad4 Protein/metabolism
مستخلص: Objective: Somatic KRAS mutations have been identified in the majority of brain arteriovenous malformations (bAVMs), and subsequent in vivo experiments have confirmed that KRAS mutation in endothelial cells (ECs) causes AVMs in mouse and zebrafish models. Our previous study demonstrated that the KRAS G12D mutant independently induced the endothelial-mesenchymal transition (EndMT), which was reversed by treatment with the lipid-lowering drug lovastatin. However, the underlying mechanisms of action were unclear.
Methods: We used human umbilical vein ECs (HUVECs) overexpressing the KRAS G12D mutant for Western blotting, quantitative real-time PCR, and immunofluorescence and wound healing assays to evaluate the EndMT and determine the activation of downstream pathways. Knockdown of SMAD4 by RNA interference was performed to explore the role of SMAD4 in regulating the EndMT. BAVM ECs expressing the KRAS G12D mutant were obtained to verify the SMAD4 function. Finally, we performed a coimmunoprecipitation assay to probe the mechanism by which lovastatin affects SMAD4.
Results: HUVECs infected with KRAS G12D adenovirus underwent the EndMT. Transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signalling pathways were activated in the KRAS G12D -mutant HUVECs and ECs in bAVM tissue. Knocking down SMAD4 expression in both KRAS G12D -mutant HUVECs and ECs in bAVM tissues inhibited the EndMT. Lovastatin attenuated the EndMT by downregulating p-SMAD2/3, p-SMAD1/5 and acetylated SMAD4 expression in KRAS G12D -mutant HUVECs.
Conclusions: Our findings suggest that the KRAS G12D mutant induces the EndMT by activating the ERK-TGF-β/BMP-SMAD4 signalling pathway and that lovastatin inhibits the EndMT by suppressing TGF-β/BMP pathway activation and SMAD4 acetylation.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
References: Annu Rev Cell Dev Biol. 2005;21:659-93. (PMID: 16212511)
Lancet. 2014 Feb 15;383(9917):614-21. (PMID: 24268105)
FASEB J. 2020 May;34(5):7178-7191. (PMID: 32274860)
Nat Commun. 2017 Feb 09;8:14361. (PMID: 28181491)
Genes Cells. 2002 Dec;7(12):1191-204. (PMID: 12485160)
Pharmacol Rev. 2018 Jan;70(1):1-11. (PMID: 29196555)
N Engl J Med. 2018 Jan 18;378(3):250-261. (PMID: 29298116)
Circ Res. 2021 Oct 15;129(9):825-839. (PMID: 34530633)
Ann Neurol. 2021 May;89(5):926-941. (PMID: 33675084)
Circ Res. 2020 Aug 28;127(6):727-743. (PMID: 32552404)
PLoS One. 2019 Dec 31;14(12):e0226852. (PMID: 31891627)
J Am Coll Cardiol. 2019 Jan 22;73(2):190-209. (PMID: 30654892)
EMBO Rep. 2020 May 6;21(5):e48693. (PMID: 32103600)
Bioinformatics. 2010 Mar 1;26(5):589-95. (PMID: 20080505)
Clin Transl Med. 2020 Jun;10(2):e99. (PMID: 32564509)
Brain. 2019 Jan 1;142(1):23-34. (PMID: 30544177)
Nat Rev Dis Primers. 2015 May 28;1:15008. (PMID: 27188382)
Front Immunol. 2018 Feb 20;9:294. (PMID: 29515588)
Immunology. 2018 Jul;154(3):434-451. (PMID: 29331024)
Mol Cancer. 2014 Nov 26;13:254. (PMID: 25424420)
Nature. 2013 Jun 27;498(7455):492-6. (PMID: 23748444)
J Clin Invest. 2019 Jun 24;129(8):3121-3133. (PMID: 31232700)
Angiogenesis. 2019 Feb;22(1):3-13. (PMID: 30076548)
Cell Death Dis. 2019 Dec 18;10(12):955. (PMID: 31852884)
Sci Transl Med. 2014 Mar 12;6(227):227ra34. (PMID: 24622514)
Stroke. 2020 Jul;51(7):2197-2207. (PMID: 32486965)
Front Immunol. 2019 Sep 10;10:2151. (PMID: 31572371)
Oncogene. 2014 Apr 17;33(16):2134-44. (PMID: 23604119)
Nat Med. 2007 Aug;13(8):952-61. (PMID: 17660828)
Genes Dev. 2007 Oct 15;21(20):2644-58. (PMID: 17938244)
Front Oncol. 2019 Aug 27;9:809. (PMID: 31508369)
Dev Cell. 2011 Aug 16;21(2):288-300. (PMID: 21839921)
Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943)
Front Pharmacol. 2017 Jul 18;8:473. (PMID: 28769803)
Sci Signal. 2014 Sep 23;7(344):re8. (PMID: 25249658)
فهرسة مساهمة: Keywords: Arteriovenous Malformations
المشرفين على المادة: 0 (Transforming Growth Factor beta)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
0 (SMAD4 protein, human)
0 (Smad4 Protein)
0 (KRAS protein, human)
تواريخ الأحداث: Date Created: 20221123 Date Completed: 20230626 Latest Revision: 20230821
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC10359780
DOI: 10.1136/svn-2022-001700
PMID: 36418055
قاعدة البيانات: MEDLINE
الوصف
تدمد:2059-8696
DOI:10.1136/svn-2022-001700