دورية أكاديمية
أعرض في EDS

Somatic A-to-I RNA-edited RHOA isoform 2 specific-R176G mutation promotes tumor progression in lung adenocarcinoma.

التفاصيل البيبلوغرافية
العنوان: Somatic A-to-I RNA-edited RHOA isoform 2 specific-R176G mutation promotes tumor progression in lung adenocarcinoma.
المؤلفون: Chen KJ; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Huang JH; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Department of Computer Science and Engineering, University of California at Santa Cruz, Santa Cruz, California, USA., Shih JH; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan., Gu DL; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Lee SS; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan., Shen R; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan., Hsu YH; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan., Kung YC; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Wu CY; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Ho CM; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Jen HW; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Lee HY; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Lang YD; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan., Hsiao CH; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.; Department of Surgery, Cheng Hsin General Hospital, Taipei, Taiwan., Jou YS; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.; Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
المصدر: Molecular carcinogenesis [Mol Carcinog] 2023 Mar; Vol. 62 (3), pp. 348-359. Date of Electronic Publication: 2022 Dec 01.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8811105 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2744 (Electronic) Linking ISSN: 08991987 NLM ISO Abbreviation: Mol Carcinog Subsets: MEDLINE
أسماء مطبوعة: Publication: <2005- > : [Hoboken, N.J.] : Wiley-Liss
Original Publication: New York : Alan R. Liss, Inc., c1988-
مواضيع طبية MeSH: Adenocarcinoma of Lung*/genetics , Lung Neoplasms*/genetics, Humans ; RNA ; Proteomics ; Adenosine ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Guanosine Triphosphate ; Inosine ; Mutation ; Cell Proliferation/genetics ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; rhoA GTP-Binding Protein/genetics ; rhoA GTP-Binding Protein/metabolism
مستخلص: Adenosine-to-inosine (A-to-I) RNA editing is the most common posttranscriptional editing to create somatic mutations and increase proteomic diversity. However, the functions of the edited mutations are largely underexplored. To identify novel targets in lung adenocarcinoma (LUAD), we conducted a genome-wide somatic A-to-I RNA editing analysis of 23 paired adjacent normal and LUAD transcriptomes and identified 26,280 events, including known nonsynonymous AZIN1-S367G and novel RHOAiso2 (RHOA isoform 2)-R176G, tubulin gamma complex associated protein 2 (TUBGCP2)-N211S, and RBMXL1-I40 M mutations. We validated the edited mutations in silico in multiple databases and in newly collected LUAD tissue pairs with the SEQUENOM MassARRAY® and TaqMan PCR Systems. We selected RHOAiso2-R176G due to its significant level, isoform-specificity, and being the most common somatic edited nonsynonymous mutation of RHOAiso2 to investigate its roles in LUAD tumorigenesis. RHOAiso2 is a ubiquitous but low-expression alternative spliced isoform received a unique Alu-rich exon at the 3' RHOA mRNA to become an editing RNA target, leading to somatic hypermutation and protein diversity. Interestingly, LUAD patients harboring the RHOAiso2-R176G mutation were associated with aberrant RHOA functions, cancer cell proliferation and migration, and poor clinical outcomes in transcriptome analysis. Mechanistically, RHOAiso2-R176G mutation-expressing LUAD cells potentiate RHOA-guanosine triphosphate (GTP) activity to phosphorylate ROCK1/2 effectors and enhance cell proliferation and migration in vitro and increase tumor growth in xenograft and systemic metastasis models in vivo. Taken together, the RHOAiso2-R176G mutation is a common somatic A-to-I edited mutation of the hypermutated RHOA isoform 2. It is an oncogenic and isoform-specific theranostic target that activates RHOA-GTP/p-ROCK1/2 signaling to promote tumor progression.
(© 2022 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)
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فهرسة مساهمة: Keywords: A-to-I RNA editing; RHOA isoform 2 specific-R176G mutation; RHOA-GTP/ROCK1/2; SEQUENOM MassARRAY® System; lung adenocarcinoma; tumor progression
المشرفين على المادة: 63231-63-0 (RNA)
K72T3FS567 (Adenosine)
0 (Protein Isoforms)
86-01-1 (Guanosine Triphosphate)
5A614L51CT (Inosine)
124671-05-2 (RHOA protein, human)
EC 3.6.5.2 (rhoA GTP-Binding Protein)
EC 2.7.11.1 (ROCK1 protein, human)
تواريخ الأحداث: Date Created: 20221201 Date Completed: 20230208 Latest Revision: 20230419
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC10107479
DOI: 10.1002/mc.23490
PMID: 36453714
قاعدة البيانات: MEDLINE
الوصف
تدمد:1098-2744
DOI:10.1002/mc.23490