Research Paper Volume 11, Issue 1 pp 33—47
HPV-18 E2 protein downregulates antisense noncoding mitochondrial RNA-2, delaying replicative senescence of human keratinocytes
- 1 Fundación Ciencia & Vida, Santiago, Chile
- 2 Andes Biotechnologies SpA, Santiago, Chile
- 3 Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O’Higgins, Santiago, Chile
- 4 Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
- 5 Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- 6 Laboratorio de Comunicaciones Celulares (CEMC) Facultad de Medicina, Universidad de Chile, Santiago, Chile
- 7 Faculty of Medical Sciences, Universidad de Santiago de Chile, Santiago, Chile
Received: July 27, 2018 Accepted: December 6, 2018 Published: December 30, 2018
https://doi.org/10.18632/aging.101711How to Cite
Abstract
Human and mouse cells display a differential expression pattern of a family of mitochondrial noncoding RNAs (ncmtRNAs), according to proliferative status. Normal proliferating and cancer cells express a sense ncmtRNA (SncmtRNA), which seems to be required for cell proliferation, and two antisense transcripts referred to as ASncmtRNA-1 and -2. Remarkably however, the ASncmtRNAs are downregulated in human and mouse cancer cells, including HeLa and SiHa cells, transformed with HPV-18 and HPV-16, respectively. HPV E2 protein is considered a tumor suppressor in the context of high-risk HPV-induced transformation and therefore, to explore the mechanisms involved in the downregulation of ASncmtRNAs during tumorigenesis, we studied human foreskin keratinocytes (HFK) transduced with lentiviral-encoded HPV-18 E2. Transduced cells displayed a significantly extended replicative lifespan of up to 23 population doublings, compared to 8 in control cells, together with downregulation of the ASncmtRNAs. At 26 population doublings, cells transduced with E2 were arrested at G2/M, together with downregulation of E2 and SncmtRNA and upregulation of ASncmtRNA-2. Our results suggest a role for high-risk HPV E2 protein in cellular immortalization. Additionally, we propose a new cellular phenotype according to the expression of the SncmtRNA and the ASncmtRNAs.