Abstract
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.
Highlights
Age is a major risk factor in the development of cancer [1]
Given the pro-tumorigenic nature of OPN and its unique regulation among studied senescence-associated secretory phenotype (SASP) factors, we sought to determine the mechanism of OPN regulation during senescence
While the +86 to -135 nucleotide region of the promoter had only ~two-fold increase in luciferase activity in bleomycin treated cells relative to non-senescent cells, the region spanning from +86 to -190 nucleotides had 4.9-fold increased expression in senescent compared to non-senescent fibroblasts
Summary
In addition to the accumulation of epithelial cell mutations, age-dependent changes in the stromal compartment play an important role in tumor promotion [2,3,4,5,6,7] One of these changes is the accumulation of senescent stromal cells that possess the ability to stimulate preneoplastic and neoplastic cell growth. First described as an in vitro phenomenon caused by repeated cell divisions, senescence can be caused by a number of genotoxic stresses including telomere shortening or dysfunction, DNA double strand breaks, oxidative stress, tumor suppressor expression, and oncogene activation [8,9,10]. Senescence is known to occur both in vitro and in vivo [9, 11, 15,16,17,18] where it impacts a diverse number of biologic processes including cancer
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