Dataset Information

Delineation of the HPV11E6 and HPV18E6 Pathways in Initiating Cellular Transformation.

ABSTRACT: Although high-risk human papillomaviruses (HPVs) are the major risk factors for cervical cancer they have been associated with several other cancers, such as head and neck and oral cancers. Since integration of low-risk HPV11 DNA has been demonstrated in esophageal tumor genomes, this study compared the effects of low-risk HPV11E6 and high-risk HPV18E6 on cellular gene expression. The HPV11E6 and HPV18E6 genes were cloned into an adenoviral vector and expressed in human keratinocytes (HaCaT) in order to investigate early events and to eliminate possible artifacts introduced by selective survival of fast growing cells in stable transfection experiments. HPV11E6 had very little effect on p21 and p53 gene expression, while HPV18E6 resulted in a marked reduction in both these proteins. Both HPV11E6 and HPV18E6 enabled growth of colonies in soft agar, but the level of colony formation was higher in HPV18E6 infected cells. DNA microarray analysis identified significantly differentially regulated genes involved in the cellular transformation signaling pathways. These findings suggest that HPV11E6 and HPV18E6 are important in initiating cellular transformation via deregulation of signaling pathways such as PI3K/AKT and pathways that are directly involved in DNA damage repair, cell survival, and cell proliferation. This study shows that the low-risk HPV11E6 may have similar effects as the high-risk HPV18E6 during the initial stages of infection, but at a much reduced level.

SUBMITTER: Mwapagha LM

PROVIDER: S-EPMC5672010 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Delineation of the HPV11E6 and HPV18E6 Pathways in Initiating Cellular Transformation.

Mwapagha Lamech M LM Tiffin Nicki N Parker M Iqbal MI

Frontiers in oncology 20171101

Although high-risk human papillomaviruses (HPVs) are the major risk factors for cervical cancer they have been associated with several other cancers, such as head and neck and oral cancers. Since integration of low-risk HPV11 DNA has been demonstrated in esophageal tumor genomes, this study compared the effects of low-risk HPV11E6 and high-risk HPV18E6 on cellular gene expression. The HPV11E6 and HPV18E6 genes were cloned into an adenoviral vector and expressed in human keratinocytes (HaCaT) in ...[more]

PMID: 29164058

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Project description:Sarcomas are highly aggressive cancers of mesenchymal origin whose clinical management is highly complex. This is partly due to a lack of understanding of the molecular mechanisms underpinning the transformation of mesenchymal stromal/stem cells (MSCs) which are presumed to be the sarcoma-initiating cells. c-Myc is amplified/overexpressed in a range of sarcomas where it has an established oncogenic role and there is evidence that it contributes to the malignant transformation of MSCs. T-box transcription factor 3 (TBX3) is upregulated by c-Myc in a host of sarcoma subtypes where it promotes proliferation, tumor formation, migration, and invasion. This study investigated whether TBX3 is a c-Myc target in human MSCs (hMSCs) and whether overexpressing TBX3 in hMSCs can phenocopy c-Myc overexpression to promote malignant transformation. Using siRNA, qRT-PCR, luciferase reporter and chromatin-immunoprecipitation assays, we show that c-Myc binds and directly activates TBX3 transcription in hMSCs at a conserved E-box motif. When hMSCs were engineered to stably overexpress TBX3 using lentiviral gene transfer and the resulting cells characterised in 2D and 3D, the overexpression of TBX3 was shown to promote self-renewal, bypass senescence, and enhance proliferation which corresponded with increased levels of cell cycle progression markers (cyclin A, cyclin B1, CDK2) and downregulation of the p14ARF/MDM2/p53 tumor suppressor pathway. Furthermore, TBX3 promoted the migratory and invasive ability of hMSCs which associated with increased levels of markers of migration (Vimentin, SLUG, SNAIL, TWIST1) and invasion (MMP2, MMP9). Transcriptomic analysis revealed that genes upregulated upon TBX3 overexpression overlapped with c-myc targets, were involved in cell cycle progression, and were associated with sarcomagenesis. Together, the data described indicate that the c-Myc/TBX3 oncogenic molecular pathway may be a key mechanism that transforms hMSCs into sarcomas.

Dataset Information

Delineation of the HPV11E6 and HPV18E6 Pathways in Initiating Cellular Transformation.

Publications

Delineation of the HPV11E6 and HPV18E6 Pathways in Initiating Cellular Transformation.

Similar Datasets

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