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Updated: Jan 31, 2026
Characterization of In Vitro Differentiation of Human Primary Keratinocytes by RNA-Seq Analysis
Published on: May 16, 2020
HPV-18 E2 protein downregulates antisense noncoding mitochondrial RNA-2, delaying replicative senescence of human
Claudio Villota1,2,3, Manuel Varas-Godoy4, Emanuel Jeldes1,2,5
1Fundación Ciencia & Vida, Santiago, Chile.
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.
Insights
Mitochondrial noncoding RNAs (ncmtRNAs) show altered expression in cancer. High-risk HPV E2 protein may contribute to cellular immortalization by downregulating antisense ncmtRNAs, suggesting a new phenotype based on ncmtRNA expression.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Mitochondrial noncoding RNAs (ncmtRNAs) exhibit differential expression based on cellular proliferative status.
- Sense ncmtRNA (SncmtRNA) and two antisense ncmtRNAs (ASncmtRNAs) are expressed in proliferating and cancer cells, with ASncmtRNAs downregulated in cancer.
- High-risk Human Papillomavirus (HPV) E2 protein is implicated as a tumor suppressor.
Purpose of the Study:
- To investigate the mechanisms behind ASncmtRNA downregulation during tumorigenesis.
- To explore the role of HPV E2 protein in cellular immortalization and its effect on ncmtRNA expression.
Main Methods:
- Transduction of human foreskin keratinocytes (HFK) with lentiviral-encoded HPV-18 E2.
- Monitoring of cellular replicative lifespan and cell cycle progression (G2/M arrest).
- Analysis of SncmtRNA and ASncmtRNA expression levels.
Main Results:
- HPV-18 E2 transduction extended HFK replicative lifespan and downregulated ASncmtRNAs.
- At later population doublings, E2-transduced cells showed G2/M arrest, E2 and SncmtRNA downregulation, and ASncmtRNA-2 upregulation.
- These findings suggest a role for HPV E2 in cellular immortalization.
Conclusions:
- High-risk HPV E2 protein may play a role in cellular immortalization.
- A novel cellular phenotype, defined by SncmtRNA and ASncmtRNA expression patterns, is proposed.
- ASncmtRNA downregulation is linked to HPV-induced transformation and cellular immortalization.
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