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

人MEX3蛋白家族包括四个rna结合蛋白（rbp），称为MEX3A-D。MEX3蛋白共享一个保守结构域组织，包括两个n端RNA结合hnrnpk同源（KH）结构域、扩展的内在无序区（IDRs）和一个c端RING结构域，涉及e3连接酶介导的蛋白质泛素化。因此，据报道，MEX3蛋白在调节RNA命运以及蛋白质表达、功能和周转方面发挥双重作用，可能相互关联。在初步分析中，我们发现了在各种实体癌症中，MEX3A强烈的癌胎表达模式严重上调，并且MEX3A丰度升高与生存率降低相关。这在肺腺癌（LUAD）中最为突出。在luad衍生的肿瘤细胞中，MEX3A的缺失/缺失会损害肿瘤细胞的增殖、自我更新、抗瘤性和迁移，并严重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池在体内消耗MEX3A严重降低了异种移植肿瘤的生长。我们的研究表明，MEX3A的促癌作用依赖于编码细胞周期调节因子的mrna的稳定，并促进肿瘤抑制因子TP53的泛素化依赖性衰变。综上所述，这些发现表明，MEX3A是一种强有力的促癌性癌胎RBP，在癌症治疗中具有潜在的治疗靶点。在RU5433框架内提出的研究旨在描述MEX3A在LUAD和其他癌症中功能的分子机制和关键效应通路。为了在体内进行评估，我们建立了条件LSL-MEX3A （lox-stop-lox）肺癌小鼠模型，以探索MEX3A与KRAS和TP53解除调控协同作用的致瘤作用。鉴于MEX3A的双重作用，该研究计划将以RNA/ rbp为中心的肿瘤生物学（h<s:1> ttelmaier）和以结构/修饰为重点的蛋白质质谱（Sinz）的跨学科专业知识结合起来。这种互补的专业知识将有助于破译MEX3A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。

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.