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  • DKFZ Publication Database  (2)
  • COMPARATIVE GENOMIC HYBRIDIZATION  (1)
  • COMPLEX  (1)
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  • DKFZ Publication Database  (2)
  • 1
    Keywords: IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; cervical intraepithelial neoplasia ; SQUAMOUS-CELL CARCINOMA ; UTERINE CERVIX ; RECURRENT PATTERN ; DNA COPY NUMBER ; EXPRESSION PROFILES ; TELOMERASE RNA GENE ; INVASIVE CANCER
    Abstract: Background: Overexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer. Methods: We performed a systematic literature review and meta-analysis of studies listed in PubMed that analysed chromosomal copy number alterations by comparative genomic hybridisation (CGH) in HPV-positive and -negative cancers or premalignant lesions of the anogenital tract (cervix, anus, vagina, penis and vulva). Findings: Data were extracted and analysed from 32 studies. The most common alterations in cervical squamous cell carcinoma (SCC) (12 studies, 293 samples) were gains at 3q with a rate of 0.55 (95% confidence interval (CI) 0.43-0.70), losses at 3p (0.36, 95%CI 0.27-0.48) and losses at 11q (0.33, 95%CI 0.26-0.43). Gains at 3q were particularly frequent in HPV16-positive cervical SCC (0.84, 95%CI 0.78-0.90). Also more than one quarter of high grade cervical intraepithelial neoplasia (CIN) harboured gains of 3q (0.27, 95%CI 0.20-0.36), but the rate in low grade CIN was low (0.02, 95%CI 0.00-0.09). For HPV-associated vulvar SCC (four studies, 30 samples) the same common alterations as in cervical SCC were reported. Studies on non-cervical and non-vulvar SCC and premalignant lesions of the lower genital tract are scarce. Interpretation: 3q gains were most frequently found in HPV16-positive cervical SCC. The results suggest the selection of HPV-transformed cell clones harbouring 3q gains in high grade premalignant lesions, while alterations in low grade lesions are rare.
    Type of Publication: Journal article published
    PubMed ID: 24054023
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; CELL ; Germany ; INHIBITION ; PATHWAY ; DEATH ; PROTEIN ; RNA ; transcription ; ACTIVATION ; COMPLEX ; COMPLEXES ; FAMILY ; nuclear bodies ; COMPONENT ; MAMMALIAN-CELLS ; MITOCHONDRIA ; TRANSLOCATION ; GLUCOCORTICOID-RECEPTOR ; FLICE ; PML ; CD95 ; RE ; FAMILIES ; INTERFERENCE ; RNA INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; senescence ; death receptor ; SIGNALS ; FLASH ; CD95 (Fas/APO-1)
    Abstract: Caspase-8-binding protein FLICE-associated huge protein ( FLASH) has been proposed to regulate death receptor CD95-induced apoptosis through facilitating caspase-8 activation at the death-inducing signaling complex. Here, we found that FLASH interacts with the PML nuclear body component Sp100 and predominantly resides in the nucleus and nuclear bodies (NBs). In response to CD95 activation, FLASH leaves the NBs and translocates into the cytoplasm where it accumulates at mitochondria. The nucleo-cytoplasmic translocation of FLASH requires CD95-induced caspase activation and is facilitated by the Crm1-dependent nuclear export pathway. Downregulation of FLASH by RNA interference or inhibition of its nucleocytoplasmic shuttling reduced CD95-induced apoptosis. Furthermore, we show that the adenoviral anti-apoptotic Bcl-2 family member E1B19K traps FLASH and procaspase-8 in a ternary complex at mitochondria, thereby blocking CD95-induced caspase-8 activation. Knock-down of Sp100 potentiated CD95-activated apoptosis through enhancing nucleo-cytoplasmic FLASH translocation. In summary, our findings suggest that CD95 signals via a previously unrecognized nuclear pathway mediated by nucleo-cytoplasmic translocation of FLASH
    Type of Publication: Journal article published
    PubMed ID: 17245429
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