Sox4 links tumor suppression to accelerated aging in mice [Telogen]

Sox4 is a transcription factor expressed during embryonic development and some adult tissues such as lymphoid organs, pancreas, intestine and skin. During embryogenesis, Sox4 regulates the survival of mesenchymal and neural progenitors, lymphocyte and myeloid differentiation, and pancreatic, bone and cardiac development. Aberrantly increased Sox4 expression is linked to malignant transformation and metastasis in several types of human cancer. To study the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display a plethora of age-related degenerative disorders and reduced spontaneous cancer incidence, indicating a role for this protein in maintaining adult tissue homeostasis and in tumor growth. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO) in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and DNA damage accumulation, accompanied by resistance to chemical carcinogenesis. These phenotypes correlate with downregulation of cell cycle, DNA repair and skin stem cell genes in the absence of Sox4. Altogether, these findings highlight the importance of Sox4 in adult tissue homeostasis and cancer. Sox4 WT and cKO (conditional KO in skin) skin was collected for microarray hybridization, to study the contribution of Sox4 to skin homeostasis in basal conditions (Telogen)Sox4是一种转录因子（transcription factor），在胚胎发育过程及淋巴器官、胰腺、肠道与皮肤等成体组织中均有表达。胚胎发生阶段，Sox4可调控间充质与神经祖细胞的存活、淋巴细胞及髓系细胞的分化，并参与胰腺、骨骼与心脏的发育。异常升高的Sox4表达与多种人类癌症的恶性转化及转移密切相关。为研究Sox4在成体生物体中的功能，我们首先构建了全身Sox4表达降低的小鼠模型。该模型小鼠表现出诸多年龄相关性退行性病症，且自发性癌症发生率降低，提示该蛋白在维持成体组织稳态与肿瘤生长中发挥关键作用。为专门探究Sox4在成体干细胞中的功能，我们在复层上皮（stratified epithelia）中条件性敲除了Sox4（Sox4cKO）。Sox4cKO小鼠表现出皮肤干细胞静息态增强与DNA损伤积累，并伴随化学致癌抗性。这些表型与Sox4缺失状态下细胞周期、DNA修复及皮肤干细胞相关基因的下调存在显著关联。综上，上述研究结果凸显了Sox4在成体组织稳态与癌症发生发展中的重要性。我们收集了Sox4野生型（WT）与皮肤条件性敲除（cKO）小鼠的皮肤样本，用于微阵列杂交（microarray hybridization）实验，以探究基础状态下（毛囊休止期Telogen）Sox4对皮肤稳态的调控作用。