IMP-Research Institute of Molecular Pathology, Vienna, Austria.
Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
PLoS One. 2023 Sep 15;18(9):e0286256. doi: 10.1371/journal.pone.0286256. eCollection 2023.
FAM3C/ILEI is an important factor in epithelial-to-mesenchymal transition (EMT) induction, tumor progression and metastasis. Overexpressed in many cancers, elevated ILEI levels and secretion correlate with poor patient survival. Although ILEI's causative role in invasive tumor growth and metastasis has been demonstrated in several cellular tumor models, there are no available transgenic mice to study these effects in the context of a complex organism. Here, we describe the generation and initial characterization of a Tet-ON inducible Fam3c/ILEI transgenic mouse strain. We find that ubiquitous induction of ILEI overexpression (R26-ILEIind) at weaning age leads to a shortened lifespan, reduced body weight and microcytic hypochromic anemia. The anemia was reversible at a young age within a week upon withdrawal of ILEI induction. Vav1-driven overexpression of the ILEIind transgene in all hematopoietic cells (Vav-ILEIind) did not render mice anemic or lower overall fitness, demonstrating that no intrinsic mechanisms of erythroid development were dysregulated by ILEI and that hematopoietic ILEI hyperfunction did not contribute to death. Reduced serum iron levels of R26-ILEIind mice were indicative for a malfunction in iron uptake or homeostasis. Accordingly, the liver, the main organ of iron metabolism, was severely affected in moribund ILEI overexpressing mice: increased alanine transaminase and aspartate aminotransferase levels indicated liver dysfunction, the liver was reduced in size, showed increased apoptosis, reduced cellular iron content, and had a fibrotic phenotype. These data indicate that high ILEI expression in the liver might reduce hepatoprotection and induce liver fibrosis, which leads to liver dysfunction, disturbed iron metabolism and eventually to death. Overall, we show here that the novel Tet-ON inducible Fam3c/ILEI transgenic mouse strain allows tissue specific timely controlled overexpression of ILEI and thus, will serve as a versatile tool to model the effect of elevated ILEI expression in diverse tissue entities and disease conditions, including cancer.
FAM3C/ILEI 是上皮间质转化 (EMT) 诱导、肿瘤进展和转移的重要因素。在许多癌症中过表达，ILEI 水平的升高和分泌与患者预后不良相关。虽然在几种细胞肿瘤模型中已经证明了 ILEI 在侵袭性肿瘤生长和转移中的因果作用，但没有可用的转基因小鼠来研究复杂生物体中的这些影响。在这里，我们描述了 Tet-ON 诱导型 Fam3c/ILEI 转基因小鼠品系的产生和初步特征。我们发现，在断奶时普遍诱导 ILEI 过表达 (R26-ILEIind) 会导致寿命缩短、体重减轻和小细胞低色素性贫血。在 ILEI 诱导停止后的一周内，年轻时贫血可逆转。Vav1 驱动的所有造血细胞中 ILEIind 转基因的过表达 (Vav-ILEIind) 不会使小鼠贫血或整体适应能力降低，这表明 ILEI 没有调节红细胞生成的内在机制，造血 ILEI 功能亢进也不会导致死亡。R26-ILEIind 小鼠的血清铁水平降低表明铁摄取或体内平衡出现故障。因此，铁代谢的主要器官肝脏在濒死的 ILEI 过表达小鼠中受到严重影响：丙氨酸转氨酶和天冬氨酸转氨酶水平升高表明肝功能障碍，肝脏缩小，凋亡增加，细胞内铁含量减少，并有纤维化表型。这些数据表明，肝脏中高 ILEI 表达可能降低肝保护作用并诱导肝纤维化，导致肝功能障碍、铁代谢紊乱，最终导致死亡。总之，我们在这里表明，新型 Tet-ON 诱导型 Fam3c/ILEI 转基因小鼠品系允许组织特异性、适时、可控的 ILEI 过表达，因此将成为一种通用工具，可用于模拟 ILEI 表达升高在多种组织实体和疾病状态（包括癌症）中的作用。
