The Molecular function of ecto 5' nucleotidase in fusion-negative rhabdomyosarcoma

融合阴性横纹肌肉瘤中5端核苷酸酶的分子功能

基本信息

批准号：
10615694
负责人：
Karla Gabriela Cano Hernandez
金额：
$ 3.69万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615694
关键词：
5&apos -Nucleotidase ADORA2A gene AKT Signaling Pathway Adenosine Adenosine Monophosphate Affect Agonist Balanced Chromosomal Translocation Binding Binding Sites Categories Cell Differentiation process Cell Surface Proteins Cells ChIP-seq Chemicals Chemotherapy and/or radiation Childhood Soft Tissue Sarcoma Chimeric Proteins Development Disease-Free Survival Doxycycline Enzymes Event FOXO1A gene Genes Genetic Transcription Genome Goals Growth Human In Vitro Invaded Knowledge Malignant Neoplasms Molecular Muscle Mutation Myoblasts Neoplasm Metastasis Nucleotidases Oncogenic Operative Surgical Procedures PI3K/AKT Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phenocopy Phenotype Primary carcinoma of the liver cells Production Proteins Purinergic P1 Receptors Recurrence Regulation Repression Research Rhabdomyosarcoma Role Signal Pathway Survival Rate System Testing Therapeutic WNT Signaling Pathway Xenograft procedure blocking factor cell growth driver mutation gain of function improved in vivo inhibitor insight knock-down loss of function malignant breast neoplasm melanoma mouse model mutant myogenesis neoplastic cell novel therapeutic intervention novel therapeutics overexpression prevent programs therapeutic target transcription factor transcriptome sequencing tumor tumor growth tumor progression

项目摘要

Project Summary/Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma characterized by the lack of myogenic differentiation. RMS is divided in two molecular categories: fusion positive (FP-RMS) carrying a balanced chromosomal translocation generating an oncogenic Pax3-FOXO1 or Pax7-FOXO1 protein, and fusion negative (FN-RMS) that does not include the fusion event. Current treatments for FN-RMS remain poor and the long-term event-free survival rate for FN-RMS metastatic patients is below 30%. TWIST2 transcription factor represses myogenesis by inhibiting MyoD function and knockdown of TWIST2 in FN-RMS is shown to inhibit tumor cell growth and enhance myogenic differentiation. To understand the mechanisms underlying TWIST2 function in FN-RMS, we sought to identify its direct transcriptional targets. Among them, we identified NT5E, encoding an ecto 5’-nucleotidase, as a direct target gene of TWIST2. NT5E’s main role is to convert adenosine- monophosphate to adenosine in the purinergic signaling pathway. NT5E has been shown to promote cancer progression, invasion and metastasis in human melanoma and breast cancer. However, it’s possible role in FN- RMS has not been explored. In this proposal, we hypothesize that NT5E contributes to FN-RMS tumor formation and progression through the activation of the purinergic signaling pathway. To test this hypothesis, we will investigate the contribution of NT5E expression to the pathogenesis of FN-RMS in vitro and in vivo. Then, we will delineate the molecular mechanism whereby NT5E promotes FN-RMS. Completion of this research plan will push the boundaries of our knowledge regarding the role of NT5E in FN-RMS pathogenesis with the ultimate goal of developing novel therapeutic strategies for FN-RMS.

项目概要/摘要横纹肌肉瘤 (RMS) 是一种侵袭性儿童软组织肉瘤，其特征是缺乏肌源性分化分为两个分子类别：融合阳性（FP-RMS）携带平衡染色体易位产生致癌 Pax3-FOXO1 或 Pax7-FOXO1 蛋白，并融合阴性（FN-RMS），不包括融合事件，目前 FN-RMS 的治疗效果仍然较差。 FN-RMS 转移患者的长期无事件生存率低于 30%。通过抑制 MyoD 功能来抑制肌生成，并且 FN-RMS 中 TWIST2 的敲低被证明可以抑制肿瘤细胞生长和增强肌原性分化了解 TWIST2 的机制。 FN-RMS 中的功能，我们试图确定其直接转录靶标，其中我们确定了 NT5E，编码胞外 5’-核苷酸酶，作为 TWIST2 的直接靶基因，其主要作用是将腺苷- NT5E 嘌呤信号通路中的单磷酸盐转化为腺苷已被证明可促进癌症。然而，它可能在 FN- 中发挥作用。在此提案中，我们尚未探讨 RMS，因为 NT5E 有助于 FN-RMS 肿瘤形成。为了验证这一假设，我们将通过激活嘌呤信号通路来进行进展。然后，我们在体外和体内研究了 NT5E 表达对 FN-RMS 发病机制的贡献。将描绘NT5E促进FN-RMS的分子机制完成本研究计划。突破我们关于 NT5E 在 FN-RMS 发病机制中的作用的知识界限开发新的 FN-RMS 治疗策略的目标。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CD73 contributes to the pathogenesis of fusion-negative rhabdomyosarcoma through the purinergic signaling pathway.

CD73 通过嘌呤信号通路参与融合阴性横纹肌肉瘤的发病机制。

DOI：
10.1073/pnas.2315925121
发表时间：
2024-01-16
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Karla Cano Hern;ez;ez;Akansha M Shah;Victor A Lopez;V. Tagliabracci;Kenian Chen;Lin Xu;R. Bassel;Eric N. Olson;Ning Liu
通讯作者：
Ning Liu