Dataset Information

HPV16 integration probably contributes to cervical oncogenesis through interrupting tumor suppressor genes and inducing chromosome instability.

ABSTRACT:

Background

The integration of human papilloma virus (HPV) into host genome is one of the critical steps that lead to the progression of precancerous lesion into cancer. However, the mechanisms and consequences of such integration events are poorly understood. This study aims to explore those questions by studying high risk HPV16 integration in women with cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (SCC).

Methods

Specifically, HPV integration status of 13 HPV16-infected patients were investigated by ligation-mediated PCR (DIPS-PCR) followed by DNA sequencing.

Results

In total, 8 HPV16 integration sites were identified inside or around genes associated with cancer development. In particular, the well-studied tumor suppressor genes SCAI was found to be integrated by HPV16, which would likely disrupt its expression and therefore facilitate the migration of tumor. On top of that, we observed several cases of chromosome translocation events coincide with HPV integration, which suggests the existence of chromosome instability. Additionally, short overlapping sequences were observed between viral derived and host derived fragments in viral-cellular junctions, indicating that integration was mediated by micro homology-mediated DNA repair pathway.

Conclusions

Overall, our study suggests a model in which HPV16 might contribute to oncogenesis not only by disrupting tumor suppressor genes, but also by inducing chromosome instability.

SUBMITTER: Zhao JW

PROVIDER: S-EPMC5123399 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

HPV16 integration probably contributes to cervical oncogenesis through interrupting tumor suppressor genes and inducing chromosome instability.

Zhao Jun-Wei JW Fang Fang F Guo Yi Y Zhu Tai-Lin TL Yu Yun-Yun YY Kong Fan-Fei FF Han Ling-Fei LF Chen Dong-Sheng DS Li Fang F

Journal of experimental & clinical cancer research : CR 20161125 1

<h4>Background</h4>The integration of human papilloma virus (HPV) into host genome is one of the critical steps that lead to the progression of precancerous lesion into cancer. However, the mechanisms and consequences of such integration events are poorly understood. This study aims to explore those questions by studying high risk HPV16 integration in women with cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (SCC).<h4>Methods</h4>Specifically, HPV integration statu ...[more]

PMID: 27884161

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Project description:BackgroundFerroptosis, a newly identified form of regulated cell death triggered by small molecules or specific conditions, plays a significant role in virus-associated carcinogenesis. However, whether tumours arising after high-risk HPV integration are associated with ferroptosis is unexplored and remains enigmatic.MethodsHigh-risk HPV16 integration was analysed by high-throughput viral integration detection (HIVID). Ferroptosis was induced by erastin, and the levels of ferroptosis were assessed through the measurement of lipid-reactive oxygen species (ROS), malondialdehyde (MDA), intracellular Fe2+ level and transmission electron microscopy (TEM). Additionally, clinical cervical specimens and an in vivo xenograft model were utilized for the study.ResultsExpression of HPV16 integration hot spot c-Myc negatively correlates with ferroptosis during the progression of cervical squamous cell carcinoma (CSCC). Further investigation revealed that the upregulated oncogene miR-142-5p in HPV16-integrated CSCC cells served as a critical downstream effector of c-Myc in its target network. Inhibiting miR-142-5p significantly decreased the ferroptosis-suppressing effect mediated by c-Myc. Through a combination of computational and experimental approaches, HOXA5 was identified as a key downstream target gene of miR-142-5p. Overexpression of miR-142-5p suppressed HOXA5 expression, leading to decreased accumulation of intracellular Fe2+ and lipid peroxides (ROS and MDA). HOXA5 increased the sensitivity of CSCC cells to erastin-induced ferroptosis via transcriptional downregulation of SLC7A11, a negative regulator of ferroptosis. Importantly, c-Myc knockdown increased the anti-tumour activity of erastin by promoting ferroptosis both in vitro and in vivo.ConclusionsCollectively, these data indicate that HPV16 integration hot spot c-Myc plays a novel and indispensable role in ferroptosis resistance by regulating the miR-142-5p/HOXA5/SLC7A11 signalling axis and suggest a potential therapeutic approach for HPV16 integration-related CSCC.

Dataset Information

HPV16 integration probably contributes to cervical oncogenesis through interrupting tumor suppressor genes and inducing chromosome instability.

Background

Methods

Results

Conclusions

Publications

HPV16 integration probably contributes to cervical oncogenesis through interrupting tumor suppressor genes and inducing chromosome instability.

Similar Datasets

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