The role and target potential of the RNA-binding protein MEX3A in lung adenocarcinoma

RNA结合蛋白MEX3A在肺腺癌中的作用和靶点潜力

• 批准号: 510828787
• 负责人: Professor Dr. Stefan Hüttelmaier
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510828787?language=en
• 关键词: role; target; potential; RNA; binding

The human MEX3 protein family comprises four RNA-binding proteins (RBPs), termed MEX3A-D. MEX3 proteins share a conserved domain organization, including two N-terminal RNA binding HNRNPK-homology (KH) domains, expanded intrinsically disordered regions (IDRs) and a C-terminal RING domain, implicated in E3-ligase mediated protein ubiquitination. Accordingly, MEX3 proteins were reported to serve dual, probably interconnected roles in modulating RNA fate as well as protein expression, function and turnover. In preliminary analyses, we identified a strong oncofetal pattern of expression for MEX3A with severe upregulation in various solid cancers and association of elevated MEX3A abundance with reduced survival probability. This was most prominent in lung adenocarcinoma (LUAD). In LUAD-derived tumor cells, MEX3A depletion/deletion impairs proliferation, self-renewal, anoikis resistance as well as migration and substantially interferes with tumor growth in subcutaneous xenograft models. Strikingly, the in vivo depletion of MEX3A via nanoparticle-delivered siRNA pools severely reduced xenograft tumor growth. Our studies suggest that pro-oncogenic roles of MEX3A rely on the stabilization of mRNAs encoding cell cycle regulators and promoting the ubiquitination-dependent decay of the tumor suppressor TP53. Collectively, these findings indicate that MEX3A is a potent pro-oncogenic oncofetal RBP with therapeutic target potential in cancer treatment. The studies proposed within the RU5433 framework aim to delineate the molecular mechanisms and key effector pathways underlying MEX3A function in LUAD and other cancers. For in vivo evaluation, we have established conditional LSL-MEX3A (lox-stop-lox) lung cancer mouse models to explore the pro-tumorigenic roles of MEX3A in synergy with KRAS and TP53 deregulation. In view of the dual roles of MEX3A, the research plan bundles interdisciplinary expertise in RNA/RBP-centered tumor biology (Hüttelmaier) and structural/modification-focused protein mass spectrometry (Sinz). This complementary expertise will allow to decipher the molecular mechanisms underlying MEX3A function in cancer to ultimately explore its therapeutic target potential in cancer treatment.

人MEX 3蛋白家族包括四种RNA结合蛋白（RBP），称为MEX 3A-D。MEX 3蛋白共有一个保守的结构域组织，包括两个N-末端RNA结合HNRNPK同源（KH）结构域，扩展的固有无序区（IDR）和一个C-末端RING结构域，涉及E3连接酶介导的蛋白泛素化。因此，据报道，MEX 3蛋白在调节RNA命运以及蛋白质表达、功能和周转中起双重的、可能相互关联的作用。在初步分析中，我们确定了MEX 3A在各种实体癌中具有强烈的癌胚表达模式，并且MEX 3A丰度升高与生存概率降低相关。这在肺腺癌（LUAD）中最为突出。在LUAD衍生的肿瘤细胞中，MEX 3A消耗/缺失损害增殖、自我更新、失巢凋亡抗性以及迁移，并且实质上干扰皮下异种移植模型中的肿瘤生长。引人注目的是，通过纳米颗粒递送的siRNA池体内消耗MEX 3A严重降低了异种移植肿瘤的生长。我们的研究表明，MEX 3A的促癌作用依赖于编码细胞周期调节因子的mRNA的稳定和促进肿瘤抑制因子TP 53的泛素化依赖性衰变。总的来说，这些发现表明MEX 3A是一种有效的原癌基因癌胎RBP，在癌症治疗中具有治疗靶点潜力。在RU 5433框架内提出的研究旨在描述LUAD和其他癌症中MEX 3A功能的分子机制和关键效应途径。对于体内评估，我们建立了条件性LSL-MEX 3A（lox-stop-lox）肺癌小鼠模型，以探索MEX 3A与KRAS和TP 53失调协同的促肿瘤发生作用。鉴于MEX 3A的双重作用，该研究计划结合了以RNA/RBP为中心的肿瘤生物学（Hüttelmaier）和以结构/修饰为中心的蛋白质质谱（Sinz）的跨学科专业知识。这种互补的专业知识将有助于破译MEX 3A在癌症中功能的分子机制，最终探索其在癌症治疗中的治疗靶点潜力。