Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, CA, United States of America.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166587. doi: 10.1016/j.bbadis.2022.166587. Epub 2022 Oct 28.
Poly zinc finger proteins (ZFP) that contain a KRAB (Krüppel-associated box) domain represent the largest class of transcription factors in higher organisms, but their roles in development and pathogenesis are largely undefined. ZFP14 (also known as ZNF531) contains thirteen zinc fingers and is highly conserved across species. Notably, we found that ZFP14 is frequently down-regulated in a multitude of human cancers, which correlates with poor prognosis of patients. Since ZFP14 has never been characterized, we generated a Zfp14-deficient mouse model to investigate the role of ZFP14 in development and pathogenesis. We showed that the mice deficient in Zfp14 had a short lifespan and were prone to diffuse large B-cell lymphoma (DLBCL), hyperplasia in multiple organs, systemic chronic inflammation, liver steatosis, and pancreatitis. Additionally, several pro-inflammatory cytokines, including IL-1β, IL18, and TNFα, were highly expressed in inflamed Zfp14 mice spleens, livers, kidneys and lungs. To determine the underlying mechanism, RNA-seq analysis was performed and showed that the loss of ZFP14 led to increased expression of inflammatory and tumor-promoting genes. Out of the various tumor-promoting genes upregulated by ZFP14 loss, the HOXA gene cluster, which is known to promote lymphomagenesis and conserved between mouse and human, is consistently induced by loss of ZFP14. Moreover, we showed that the HOXA gene expression was inversely correlated with that of ZFP14 in human cancer patients and higher HOXA1 expression was correlated with poor patient prognosis. Together, we postulate that ZFP14 suppresses lymphomagenesis and abnormal inflammatory response by maintaining proper expression of the HOXA gene cluster.
锌指蛋白（ZFP）包含 KRAB（Krüppel 相关盒）结构域，是高等生物中最大的转录因子家族之一，但它们在发育和发病机制中的作用在很大程度上尚未确定。ZFP14（也称为 ZNF531）包含 13 个锌指，在物种间高度保守。值得注意的是，我们发现 ZFP14 在多种人类癌症中经常下调，这与患者的预后不良相关。由于 ZFP14 从未被表征过，我们生成了 Zfp14 缺陷型小鼠模型来研究 ZFP14 在发育和发病机制中的作用。我们发现，Zfp14 缺陷型小鼠的寿命较短，容易发生弥漫性大 B 细胞淋巴瘤（DLBCL）、多个器官增生、全身慢性炎症、肝脂肪变性和胰腺炎。此外，几种促炎细胞因子，包括 IL-1β、IL18 和 TNFα，在炎症性 Zfp14 小鼠的脾脏、肝脏、肾脏和肺部中高度表达。为了确定潜在的机制，我们进行了 RNA-seq 分析，结果表明 ZFP14 的缺失导致促炎和促进肿瘤的基因表达增加。在 ZFP14 缺失导致上调的各种促肿瘤基因中，HOXA 基因簇已知可促进淋巴瘤发生，在小鼠和人类之间保守，是由 ZFP14 缺失一致诱导的。此外，我们表明，HOXA 基因的表达与人类癌症患者中 ZFP14 的表达呈负相关，HOXA1 表达较高与患者预后不良相关。综上所述，我们推测 ZFP14 通过维持 HOXA 基因簇的适当表达来抑制淋巴瘤的发生和异常炎症反应。
