Priority Research Paper Volume 13, Issue 4 pp 4747—4777
Insights into epithelial cell senescence from transcriptome and secretome analysis of human oral keratinocytes
- 1 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies and University of California – San Diego, La Jolla, CA 92037, USA
- 2 Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
- 3 Waitt Advanced Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
- 4 Department of Pharmacology and Moores Cancer Center, University of California – San Diego, La Jolla, CA 92093, USA
- 5 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Received: August 18, 2020 Accepted: January 21, 2021 Published: February 12, 2021https://doi.org/10.18632/aging.202658
How to Cite
Copyright: © 2021 Schwartz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Senescent cells produce chronic inflammation that contributes to the diseases and debilities of aging. How this process is orchestrated in epithelial cells, the origin of human carcinomas, is poorly understood. We used human normal oral keratinocytes (NOKs) to elucidate senescence programs in a prototype primary mucosal epithelial cell that senesces spontaneously. While NOKs exhibit several typical facets of senescence, they also display distinct characteristics. These include expression of p21WAF1/CIP1 at early passages, making this common marker of senescence unreliable in NOKs. Transcriptome analysis by RNA-seq revealed specific commonalities with and differences from cancer cells, explicating the tumor avoidance role of senescence. Repression of DNA repair genes that correlated with downregulation of E2F1 mRNA and protein was observed for two donors; a divergent result was seen for the third. Using proteomic profiling of soluble (non-vesicular) and extracellular vesicle (EV) associated secretions, we propose additions to the senescence associated secretory phenotype, including HSP60, which localizes to the surface of EVs. Finally, EVs from senescent NOKs activate interferon pathway signaling in THP-1 monocytes in a STING-dependent manner and associate with mitochondrial and nuclear DNA. Our results highlight senescence changes in epithelial cells and how they might contribute to chronic inflammation and age-related diseases.