Project description:Integration of high-risk human papillomavirus (HRHPV) into the host genome is a key event in cervical neoplastic progression. Integration is associated with deregulated expression of the viral oncogenes E6 and E7 and acquisition of a selective growth advantage.
Project description:Human papillomavirus (HPV) integration is a critical step in cervical cancer development, while the oncogenic mechanism in genome-wide transcriptional level is still poorly understood. In this study, we employed integrative analysis on multi-omics data of cervical cancer cell lines. Through HPV integration detection, super enhancer (SE) identification, SE-associated gene expression and extrachromosomal DNA (ecDNA) investigation, we aimed to explore the genome-wide transcriptional influence of HPV integration. We identified 5 high-ranking cellular super enhancers generated by HPV integration (the HPV breakpoint induced cellular super enhancers, BP-cSE), leading to intra-chromosomal and inter-chromosomal regulations of chromosomal genes. The pathway analysis showed the dysregulated chromosomal genes were correlated to cervical cancer associated pathways. Importantly, we demonstrated that BP-cSE existed in the HPV-host ecDNA, explaining above transcription alterations. Our results suggest that HPV integration generates cellular super enhancers and functions as ecDNA to regulate unconstraint transcription, expanding the tumorigenic mechanism of HPV integration and providing insights of developing new diagnostic and therapeutic strategies.
Project description:Human papillomavirus (HPV) infection related malignancy remains a severe public health problem worldwide, although HPV prophylactic vaccine has been introduced 15 years ago . HPV-associated cancers comprise 29.1% of all 2.2 million infection-related cancers, including nearly 100% of cervical cancers1 and some head and neck cancers . Cervical cancers are the 3rd most common cancer in women worldwide, HPV16 and 18 account for about 70% of cervical cancers. Moreover, high-risk HPV infection, especially HPV16 infection, is related to a proportion of head and neck epithelial carcinoma in both developed and undeveloped countries. HPV related cancers are most severe in developing countries where HPV prophylactic vaccination rates are low.In this project, we use iTRAQ8plex-labelling proteomics to comparatively study the protein contents in the tumour tissues of early and late stage cervical cancer patietns.
Project description:Integration of human papillomavirus (HPV) DNA into the host genome is a critical aetiological event in the progression from normal cervix to intraepithelial neoplasm, and finally to invasive cervical cancer. In this study, we want to know how HPV DNA physical status relates to treatment outcome for cervical carcinomas.
Project description:A panel of human fibroblasts derived from patient samples (vulval, oral, cervical and breast carcinoma and metastatic melanoma) were seperated according to their ability to generate an aligned (anisotropic) or non-aligned extracellular matrix.
Project description:Integration of human papillomavirus (HPV) DNA into the host genome is a critical aetiological event in the progression from normal cervix to intraepithelial neoplasm, and finally to invasive cervical cancer. In this study, we want to know how HPV DNA physical status relates to treatment outcome for cervical carcinomas. Cervical cancer samples were compared with normal sample. And also, we divided 39 cervical cancer patients into four groups according to HPV DNA physical status and investigated differentially expressed gene profiles in these groups using Agilent two-color experiment.
Project description:Integration of high-risk human papillomavirus (HRHPV) into the host genome is a key event in cervical neoplastic progression. Integration is associated with deregulated expression of the viral oncogenes E6 and E7 and acquisition of a selective growth advantage for cells containing integrants. Overexpression of the viral transcriptional regulator E2 from heterologous promoters has an inhibitory effect on transcription from integrated HRHPV. We therefore hypothesised that loss of E2-expressing episomes from cells in which integration had previously occurred would be required for such cells to gain a growth advantage. Using the unique W12 model of cervical squamous carcinogenesis, we show that cells containing integrated HPV16 reproducibly emerged during long-term culture when there had been a rapid fall in episome numbers. During the period of emergence it is possible to isolate single-cell clones containing an intracellular mixture of the integrant being selected and episomes at reduced load. Microarray analysis showed that episome loss was closely associated with endogenous activation of antiviral response genes that are also inducible by the type I interferon (IFN) pathway. Taken together, our results indicate that episome loss, associated with induction of antiviral response genes, is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. We conclude that cervical carcinogenesis requires not only HRHPV integration, but also loss of inhibitory episomes. Keywords: Time course, human papillomavirus, episome loss
Project description:In most cases human papillomavirus (HPV) infections are cleared from the cervical cells by the immune system itself, but in a few cases, where there is persistent HPV infection, it can lead to cervical intraepithelial neoplasia (CIN) progression and ultimately invasive cervical carcinoma. The cytopathic effect is in general accompanied by chronic inflammation, which produces inflammation cytokines that contribute to DNA damage, and at the same time, aberrations occurred in the host DNA repair mechanisms, thus lead to HPV genomic integration into the host cells which propels cell immortalization. In this study, we reported the genome-wide expression profiles of both microRNAs (miRNAs) and mRNAs from 24 cervical samples with consecutive stages of normal, CIN I (mild dysplasia) and CIN III (severe dysplasia and carcinoma in situ), and presented the SIG++ algorithm which is founded on the evolution process of intermolecular regulation change during disease progression, to identify the significant change of miRNA-mRNA regulations rather than the expression change, across different disease stages, thereupon elucidating the molecular mechanisms of increasing host genomic instability as disease progresses. As reconstructing miRNA differential networks, we found that at each stage of CIN, there respectively exists specific miRNA regulations mediating chronic inflammation persistence, genome instability and cell survival, which coordinately carrys out the integration of HPV genomes into the host cell genomes, and finally results in cell immortalization. Beyond the specific implications for cervical carcinogenesis, this work establishes a new framework for studying the biology of miRNAs in pathogenesis from the perspective of miRNA differential regulation, and helps ensure the comprehensiveness of miRNA-mediated genetic regulatory pathways. There are totally 24 clinical samples in this study comprises three stages: 7 normal cervix samples (HPV-), 9 CIN I samples (HPV+) and CIN III samples (HPV+), where normal refers to the adjacent tissue of early lesions. For each sample, its total RNA was extracted and purified, then separately hybridized to Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) and Illumina Human v2 MicroRNA Expression BeadChip, for examining the expression profiles of mRNAs and miRNAs, respectively.
Project description:Oral squamous cell carcinoma (OSCC) is highly heterogeneous and metastatic, and the mechanisms driving OSCC development, progression, and metastasis are poorly understood. We performed multiregional single-cell RNA sequencing on 268,131 cells obtained from tumor core, tumor periphery, adjacent non-tumor tissue, and metastatic lymph node samples from 10 patients with human papillomavirus (HPV)–negative metastatic OSCC.
