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Project 3: lncRNA SNHG1 and ATG7 in Basal-subtype Muscle-invasive Bladder Tumorigenesis

项目3：lncRNA SNHG1和ATG7在基底亚型肌侵袭性膀胱肿瘤发生中的作用

基本信息

批准号：
10661067
负责人：
DIANE M SIMEONE
金额：
$ 33.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-12 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10661067
关键词：
Ablation Autophagocytosis BIRC4 gene Biological Biological Markers Biological Process Bladder CD44 gene CRISPR/Cas technology Carcinogens Catabolism Cell model Cells Characteristics Chemicals Classification Data Ectopic Expression Exposure to Funding Genes Goals Human In Vitro Invaded Knock-in Mouse Knock-out Knockout Mice LoxP-flanked allele MMP2 gene MMP9 gene Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Mediator Molecular Mus Muscle Neoplasm Metastasis Nitrosamines Pathway interactions Phenotype Play Prognostic Marker RNA Resistance Resources Role Signal Pathway Signal Transduction Signaling Molecule Small Nucleolar RNA Stratification System Testing Transgenic Mice Transgenic Organisms Untranslated RNA Up-Regulation Urothelial Cell Variant Xenograft Model cancer biomarkers cancer cell cancer subtypes carcinogenesis effective therapy in vivo inhibition of autophagy inhibitor knock-down molecular subtypes mortality muscle invasive bladder cancer new therapeutic target non-muscle invasive bladder cancer novel overexpression promoter small hairpin RNA tumor progression tumorigenesis

项目摘要

PROJECT 3: SUMMARY The major goal of this project is to study the molecular mechanisms that underlie the critical steps of bladder cancer (BC) progression: invasion and metastasis. Specifically, we will focus on how autophagy-related gene 7 (ATG7)-mediated autophagy signaling drives BC cell invasion in vitro and metastasis in vivo. During the last funding period, we found that basal-subtype muscle-invasive bladder cancer (MIBC) in mice induced by bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) markedly overexpress ATG7 and long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1), and have significantly upregulated autophagy. In stark contrast, knockin mice lacking the RING domain of XIAP, which are completely resistant to BBN-induced basal MIBCs, have markedly reduced autophagy. We also found that, during BBN-mediated bladder tumorigenesis, the RING domain of XIAP is essential for SNHG1 overexpression, and that ectopic expression of SNHG1 in vitro induces autophagy and promotes BC cell invasion accompanied by upregulated ATG7, MMP2 and MMP9. Furthermore, we showed that knockdown of ATG7 strongly inhibits autophagy, abolishes BC cell invasion and reduces the expression of basal MIBC marker KRT14. These data reveal a heretofore unknown role of autophagy in basal MIBC formation. Based on these data, we hypothesize that the upregulation of SNHG1 and ATG7 by the RING domain of XIAP, and the autophagic signaling that these molecules trigger play critical roles in the genesis and progression of basal MIBC. We will test this hypothesis in three Specific Aims. Aim 1 will define the regulatory circuitry in the SNHG1/ATG7/autophagy signaling axis that is operative in basal MIBC in vitro. Aim 2 will determine the biological effects of the SNHG1/ATG7/autophagy signaling on BC cell invasion in vitro and tumorigenesis and metastasis in vivo. Aim 3 will test the hypotheses that overexpression of SNHG1 in basal urothelial cells of transgenic mice promotes basal MIBC formation, and that ablation of ATG7 in these cells of knockout mice renders mice resistant to basal MIBC formation and progression. These complementary approaches will provide definitive evidence regarding the in vivo roles of SNHG1 and ATG7 in the formation and progression of basal MIBC. While invasion and metastasis are the main reasons of the high mortality caused by MIBC, very little is known about the principal molecules or pathways that drive these crucially important biological processes. Our proposed studies that are highly focused on an important, but poorly understood signaling pathway comprising SNHG1/ATG7/autophagy should yield critical information on not only the underlying mechanisms, but also novel prognostic biomarkers to differentiate MIBC subtypes and new druggable targets to treat this aggressive form of BC.

项目3：总结