Flanagan Kevin C, Alspach Elise, Pazolli Ermira, Parajuli Shankar, Ren Qihao, Arthur Laura L, Tapia Roberto, Stewart Sheila A
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
ICCE Institute, Washington University School of Medicine, St. Louis, MO, USA.
Oncotarget. 2017 Dec 5;9(1):21-36. doi: 10.18632/oncotarget.22940. eCollection 2018 Jan 2.
Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Senescent cells, which secrete a plethora of pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), play an important role in tumor formation. Investigation into SASP regulation revealed that many but not all SASP factors are subject to NF-kB and p38MAPK regulation. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not responsive to these canonical pathways leaving the regulation of these factors an open question. We report that the transcription factor c-Myb regulates OPN, IL-6, and IL-8 in addition to 57 other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in response to senescence. Further, OPN is also regulated by the known SASP regulator C/EBPβ. In response to senescence, the full-length activating C/EBPβ isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. The importance of both c-Myb and C/EBPβ is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells.
肿瘤发生源于细胞自主性突变与相应促进肿瘤细胞生长的基质变化的共同作用。衰老细胞分泌大量被称为衰老相关分泌表型（SASP）的促肿瘤因子，在肿瘤形成中发挥重要作用。对SASP调控的研究表明，许多但并非所有SASP因子都受NF-κB和p38MAPK调控。然而，许多促肿瘤的SASP因子，包括骨桥蛋白（OPN），对这些经典途径无反应，这些因子的调控仍是一个悬而未决的问题。我们报告转录因子c-Myb除了调控57种其他SASP因子外，还调控OPN、IL-6和IL-8。OPN的调控是直接的，因为c-Myb在衰老反应中与OPN启动子结合。此外，OPN也受已知的SASP调节因子C/EBPβ调控。在衰老反应中，全长激活型C/EBPβ异构体LAP2增加与OPN、IL-6和IL-8启动子的结合。我们发现敲除任一因子都会降低衰老成纤维细胞促进肿瘤前上皮细胞生长的能力，这突出了c-Myb和C/EBPβ两者的重要性。
