Homo sapiens
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PROVIDER: PRJNA292856 | ENA |
REPOSITORIES: ENA
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Project description:Human papillomavirus (HPV) induced immortalization of human foreskin keratinocytes (HFK) is a two-step process, including 1) the bypass of replicative senescence and acquisition of an extended lifespan, and 2) the outgrowth of immortal cells. Our previous study showed that the immortalization capacity of HPV is type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. In the present study we determined how the HPV-type specific immortalization capacity relates to DNA damage induction and overall genomic instability. Early passage HFKs transduced with HPV types 16, 18, 31, 33, 35, 45, 51, 59, 66 and 70 showed an increased number of double strand DNA breaks compared to controls, without significant differences between the various HPV-types. However, immortal descendants of HPV-transduced HFKs that underwent a crisis period (HPV45-, 51-, 59-, 66- and 70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without a crisis period (HPV16-, 18-, 31-, and 35-transduced HFKs) (p<0.01). In particular, regions on chromosome 5p, 8, and 9q were significantly more frequently altered in cells with crisis. Interestingly, the hTERT locus at 5p was exclusively gained in cell lines with crisis. Chromothripsis was detected in one of the HPV16-immortalized cell lines in which multiple rearrangements within chromosome 8 resulted in a gain of c-MYC. In conclusion, the present study shows that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the immortalization capacity of the virus type. This suggests that hrHPV types with reduced immortalization capacity in vitro, as reflected by a crisis period, require more genetic host cell aberrations to trigger immortalization. DNA copy number analysis of human keratinocytes transformed by high-risk HPV
2016-08-01 | E-GEOD-72063 | biostudies-arrayexpress
Project description:Human papillomavirus (HPV) induced immortalization of human foreskin keratinocytes (HFK) is a two-step process, including 1) the bypass of replicative senescence and acquisition of an extended lifespan, and 2) the outgrowth of immortal cells. Our previous study showed that the immortalization capacity of HPV is type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. In the present study we determined how the HPV-type specific immortalization capacity relates to DNA damage induction and overall genomic instability. Early passage HFKs transduced with HPV types 16, 18, 31, 33, 35, 45, 51, 59, 66 and 70 showed an increased number of double strand DNA breaks compared to controls, without significant differences between the various HPV-types. However, immortal descendants of HPV-transduced HFKs that underwent a crisis period (HPV45-, 51-, 59-, 66- and 70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without a crisis period (HPV16-, 18-, 31-, and 35-transduced HFKs) (p<0.01). In particular, regions on chromosome 5p, 8, and 9q were significantly more frequently altered in cells with crisis. Interestingly, the hTERT locus at 5p was exclusively gained in cell lines with crisis. Chromothripsis was detected in one of the HPV16-immortalized cell lines in which multiple rearrangements within chromosome 8 resulted in a gain of c-MYC. In conclusion, the present study shows that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the immortalization capacity of the virus type. This suggests that hrHPV types with reduced immortalization capacity in vitro, as reflected by a crisis period, require more genetic host cell aberrations to trigger immortalization.
2016-08-01 | GSE72063 | GEO
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.
2013-11-02 | E-GEOD-51993 | biostudies-arrayexpress
Project description:H3K27me3 changes during immortalization of breast cells. The aim of the study was to determine whether differential epigentic state of TERT gene is involved in immortalization of breast cells. comparison of Pre-Stasis, Post-Selection, and immortal cells
2013-07-03 | E-GEOD-48456 | biostudies-arrayexpress
Project description:H3K4me3 changes during immortalization of breast cells. The aim of the study was to determine whether differential epigentic state of TERT gene is involved in immortalization of breast cells. comparison of Pre-Stasis, Post-Selection, and immortal cells
2013-07-03 | E-GEOD-48457 | biostudies-arrayexpress
Project description:DNA methylation changes during immortalization of breast cells. The aim of the study was to determine whether differential epigentic state of TERT gene is involved in immortalization of breast cells. comparison of Pre-Stasis, Post-Selection, and immortal cells
2013-07-03 | E-GEOD-48447 | biostudies-arrayexpress
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.
2013-11-02 | GSE51993 | GEO
Project description:- Gene expression changes linked to two step immortalization of human mammary epithelial cells (HMEC). - A lincRNA, MORT, associated with the mortal state, was identified - MORT is silenced by DNA methylation in immortal mammary epithelial cells Abstract: Immortality is an essential characteristic of human carcinoma cells. We recently developed an efficient, reproducible method that immortalizes human mammary epithelial cells (HMEC) in the absence of gross genomic changes by targeting two critical senescence barriers. Consistent transcriptomic changes associated with immortality were identified using microarray analysis of isogenic normal finite pre-stasis, abnormal finite post-stasis, and immortal HMECs from four individuals. 277 genes consistently changed in cells that transitioned from post-stasis to immortal. Gene ontology analysis of affected genes revealed biological processes significantly altered in the immortalization process. These immortalization-associated changes showed striking similarity to the gene expression changes seen in The Cancer Genome Atlas (TCGA) clinical breast cancer data. The most dramatic change in gene expression seen during the immortalization step was the down-regulation of an unnamed, incompletely annotated transcript that we called MORT, for mortality, since its expression was closely associated with the mortal, finite lifespan phenotype. We show here that MORT (ZNF667-AS1) is expressed in all normal finite lifespan human cells examined to date and is lost in immortalized HMEC. MORT gene silencing at the mortal/immortal boundary was due to DNA hypermethylation of its CpG island promoter. This epigenetic silencing is also seen in human breast cancer cell lines and in a majority of human breast tumor tissues. The functional importance of DNA hypermethylation in MORT gene silencing is supported by the ability of 5-aza-2’-deoxycytidine to reactivate MORT expression. Analysis of TCGA data revealed deregulation of MORT expression due to DNA hypermethylation in 15 out of the 17 most common human cancers. The epigenetic silencing of MORT in a large majority of the common human cancers suggests a potential fundamental role in cellular immortalization during human carcinogenesis.
2015-10-05 | GSE72353 | GEO
Project description:ABSTRACT Two major subgroups of head and neck squamous cell carcinomas (HNSCC) are currently distinguished based on etiology and pattern of genetic alterations; tumors with biologically active human papillomavirus (HPV) and tumors without. It is at present unclear whether additional genetically distinct subgroups exist within HPV-negative HNSCC. Aim of this study is to genetically classify HNSCC without HPV involvement and to correlate the genetically defined classes to tumor and patient characteristics. By means of array comparative genomic hybridization (aCGH) we determined DNA copy number variation in thirty-nine HPV-negative, but further unselected HNSCC. Unsupervised analysis of aCGH data distinguished two genetic groups in HPV-negative HNSCC, one characterized by a low level of chromosomal alterations (N=9), and another by a high level of chromosomal alterations (N=30). Absence of chromosomal aberrations was significantly associated with wild-type TP53, a low level of alcohol consumption, a female gender and a better prognosis. The tumors were negative for microsatellite instability. The discovery of this new class of HNSCC with unique genetic and clinical characteristics has important consequences for future basic and clinical studies.
2009-03-12 | GSE11929 | GEO