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

人类MEX3蛋白家族由四个RNA结合蛋白(RBP)组成，称为MEX3A-D。MEX3蛋白有一个保守的结构域结构，包括两个N端RNA结合HNRNPK同源(KH)结构域、扩展的固有无序区(IDR)和一个C端环域，参与E3连接酶介导的蛋白质泛素化。因此，MEX3蛋白被报道在调节RNA命运以及蛋白质的表达、功能和周转方面发挥双重的、可能相互关联的作用。在初步分析中，我们发现了MEX3A在肿瘤胎儿中的强烈表达模式，并在各种实体癌中严重上调，并发现MEX3A丰度增加与生存概率降低有关。这在肺腺癌(LUAD)中最为突出。在LUAD来源的肿瘤细胞中，MEX3A的缺失/缺失损害了肿瘤细胞的增殖、自我更新、失巢细胞抵抗和迁移，并在皮下移植模型中严重干扰了肿瘤的生长。引人注目的是，通过纳米颗粒传递的siRNA池在体内耗尽MEX3A，严重减少了异种移植瘤的生长。我们的研究表明，MEX3A的致癌作用依赖于编码细胞周期调节因子的mRNAs的稳定，并促进肿瘤抑制基因TP53的泛素化依赖的衰退。总而言之，这些发现表明MEX3A是一种有效的致癌前胎儿RBP，在癌症治疗中具有治疗靶点的潜力。在RU5433框架内提出的研究旨在描绘LUAD和其他癌症中MEX3A功能的分子机制和关键效应途径。为了进行体内评估，我们建立了条件性LSL-MEX3A(LOX-STOP-LOX)肺癌小鼠模型，以探索MEX3A在与KRAS和TP53去调控协同作用中的促肿瘤作用。鉴于MEX3A的双重作用，该研究计划融合了以RNA/RBP为中心的肿瘤生物学(Hüttelmaier)和结构/修饰为重点的蛋白质质谱仪(SINZ)的跨学科专业知识。这种互补的专业知识将使我们能够破译癌症中MEX3A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.