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  • POSITIVE CANCER-CELLS  (5)
  • BREAST-CANCER  (4)
  • CERVICAL-CANCER  (4)
Keywords
  • 1
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; INHIBITION ; GENE ; PROTEIN ; TISSUE ; CARCINOGENESIS ; DOWN-REGULATION ; E7 ; papillomavirus ; TARGET ; virus ; ELEMENT ; LESIONS ; PROMOTER ; cervical cancer ; CERVICAL-CANCER ; p53 ; GROWTH-INHIBITION ; human papillomavirus ; CANCER-CELLS ; HPV ; E6 ; ONCOGENE ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; CARCINOMAS ; POSITIVE CANCER-CELLS ; TRANSLOCATION ; OVEREXPRESSION ; REPRESSION ; RETINOIC ACID ; E6 ONCOPROTEIN ; TUMOR-SUPPRESSOR ; papillomaviruses ; LEVEL ; tumor suppressor gene ; EPITHELIUM ; USA ; oncogenes ; B-CELL ; HUMAN PAPILLOMAVIRUSES ; tumor suppressor genes ; NOV ; tumor suppressor ; Luciferase reporter ; BTG2 ; cervical cancers ; viral carcinogenesis
    Abstract: Human papillomavirus (HPV)-induced carcinogenesis is critically dependent on the activities of the viral E6 and E7 oncogenes. Here, we demonstrate that expression of the putative tumor suppressor gene B-cell translocation gene-2 (BTG2) is reinduced in HPV16- and HPV18-positive cancer cells on silencing of viral oncogene expression, indicating that BTG2 is repressed by oncogenic HPVs. Inhibition of BTG2 expression was mediated by the HPV E6 oncogene and occurred in a p53-dependent manner. Luciferase reporter gene analyses revealed that BTG2 repression takes place at the transcriptional level and is dependent on the integrity of the major p53-response element within the BTG2 promoter. Ectopic expression of BTG2 acted antiproliferative in cervical cancer cells. Tissue specimens commonly exhibited reduced BTG2 protein levels in HPV-positive high-grade lesions (CIN2/3) and cervical carcinomas, when compared with normal cervical epithelium. These findings identify the antiproliferative BTG2 gene as a novel cellular target blocked by the HPV E6 oncoprotein. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19551855
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  • 2
    Keywords: CANCER ; EXPRESSION ; INVASION ; DIFFERENTIATION ; BREAST-CANCER ; COLORECTAL-CANCER ; STEM-CELLS ; SOMATIC MUTATIONS ; ENHANCER-OF-ZESTE-HOMOLOG-2 GENE ; HISTONE METHYLTRANSFERASE ; METHYLTRANSFERASE GENE EZH2 ; NUMBERS
    Abstract: The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi) mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer
    Type of Publication: Journal article published
    PubMed ID: 21765901
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  • 3
    Keywords: HEPATOCELLULAR-CARCINOMA ; cervical cancer ; HPV ; CERVICAL-CARCINOMA CELLS ; POSITIVE CANCER-CELLS ; intraepithelial neoplasia ; vaccination ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; EPSTEIN-BARR-VIRUS ; HEPATITIS-C VIRUS ; HCV ; HIV ; EBV ; liver cancer ; EPIGENETICS ; miRNA ; HBV ; tumor viruses ; HTLV-1 ; KAPOSI-SARCOMA ; LYTIC CYCLE REPLICATION ; VIRAL E6 ONCOPROTEIN ; virus detection
    Abstract: After a long period of scepticism and disbelief, tumor viruses are today recognized as a significant cancer risk factor for humans. Much has been learned about the viral transforming mechanisms and prophylactic vaccines have been developed against 2 major tumor viruses, HBV and HPV. Yet, many important issues of tumor virology remain unresolved and exciting new ones are emerging from recent discoveries. They define future research directions for the field and include (i) novel strategies for tumor virus hunting, (ii) tumor viruses as experimental tools to study human carcinogenesis, (iii) the interplay between viruses and the world of small noncoding RNAs, (iv) epigenetic interactions between tumor viruses and the host cell, (v) the role of virus/virus interactions for viral carcinogenesis and (vi) novel strategies for prevention and therapy of virus-associated cancers. These topics are discussed by summarizing recent developments, pointing out unresolved issues and suggesting possible strategies for their solution
    Type of Publication: Journal article published
    PubMed ID: 21445966
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  • 4
    Keywords: BREAST-CANCER ; CANCER-CELLS ; CERVICAL-CARCINOMA CELLS ; HUMAN KERATINOCYTES ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; E7 ONCOPROTEIN ; E6 ONCOPROTEIN ; RNA INTERFERENCE ; EXTRACELLULAR VESICLES ; CIRCULATING MICRORNA
    Abstract: Specific types of human papillomaviruses (HPVs) cause cervical cancer. Cervical cancers exhibit aberrant cellular microRNA (miRNA) expression patterns. By genome-wide analyses, we investigate whether the intracellular and exosomal miRNA compositions of HPV-positive cancer cells are dependent on endogenous E6/E7 oncogene expression. Deep sequencing studies combined with qRT-PCR analyses show that E6/E7 silencing significantly affects ten of the 52 most abundant intracellular miRNAs in HPV18-positive HeLa cells, downregulating miR-17-5p, miR-186-5p, miR-378a-3p, miR-378f, miR-629-5p and miR-7-5p, and upregulating miR-143-3p, miR-23a-3p, miR-23b-3p and miR-27b-3p. The effects of E6/E7 silencing on miRNA levels are mainly not dependent on p53 and similarly observed in HPV16-positive SiHa cells. The E6/E7-regulated miRNAs are enriched for species involved in the control of cell proliferation, senescence and apoptosis, suggesting that they contribute to the growth of HPV-positive cancer cells. Consistently, we show that sustained E6/E7 expression is required to maintain the intracellular levels of members of the miR-17 similar to 92 cluster, which reduce expression of the anti-proliferative p21 gene in HPV-positive cancer cells. In exosomes secreted by HeLa cells, a distinct seven-miRNA-signature was identified among the most abundant miRNAs, with significant downregulation of let-7d-5p, miR-20a-5p, miR-378a-3p, miR-423-3p, miR-7-5p, miR-92a-3p and upregulation of miR-21-5p, upon E6/E7 silencing. Several of the E6/E7-dependent exosomal miRNAs have also been linked to the control of cell proliferation and apoptosis. This study represents the first global analysis of intracellular and exosomal miRNAs and shows that viral oncogene expression affects the abundance of multiple miRNAs likely contributing to the E6/E7-dependent growth of HPV-positive cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 25760330
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  • 5
    Keywords: APOPTOSIS ; PROTEIN ; INDUCTION ; ASSOCIATION ; CERVICAL-CANCER ; p53 ; POSITIVE CANCER-CELLS ; NUCLEAR-LOCALIZATION ; E6-MEDIATED DEGRADATION ; AGGRESOMES
    Abstract: Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer and other malignancies in humans. The HPV E6 oncoprotein is considered to be an attractive therapeutic target since its inhibition can lead to the apoptotic cell death of HPV-positive cancer cells. The HPV type 16 (HPV16) E6-binding peptide pep11, and variants thereof, induce cell death specifically in HPV16-positive cancer cells. Although they do not encompass the LxxLL binding motif found in cellular HPV16 E6 interaction partners, such as E6AP, the pep11 variants strongly bind to HPV16 E6 by contacting the recently identified E6AP binding pocket. Thus, these peptides can serve as prototype E6-inhibitory molecules which target the E6AP pocket. We here analyzed their intracellular interaction with HPV16 E6. By comprehensive intracellular binding studies and GST pull-down assays, we show that E6-binding competent pep11 variants induce the formation of a trimeric complex, consisting of pep11, HPV16 E6 and p53. These findings indicate that peptides, which do not contain the LxxLL motif, can reshape E6 to enable its interaction with p53. The formation of the trimeric HPV16 E6 / peptide / p53 complex was associated with an increase of endogenous HPV16 E6 protein amounts. Yet, total cellular p53 amounts were also increased, indicating that the E6 / E6AP-mediated degradation of p53 is blocked. These findings suggest that inhibition of oncogenic activities by targeting the E6AP pocket on HPV16 E6 could be a strategy for therapeutic intervention.
    Type of Publication: Journal article published
    PubMed ID: 26151636
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  • 6
    Keywords: IN-VITRO ; PROSTATE-CANCER ; POSITIVE CANCER-CELLS ; OXIDATIVE STRESS ; TRANSCRIPTIONAL REGULATION ; RNA INTERFERENCE ; NUCLEAR-LOCALIZATION SIGNAL ; HIV-1 INTEGRASE ; INTEGRASE INTERACTOR LEDGF/P75 ; DNA-END RESECTION
    Abstract: The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic.
    Type of Publication: Journal article published
    PubMed ID: 24604027
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  • 7
    Keywords: IN-VITRO ; carcinoma ; INHIBITION ; MODEL ; PROTEIN ; SUPPRESSION ; BREAST-CANCER ; TUMOR PROGRESSION ; OVEREXPRESSION ; CYCLE REGULATOR
    Abstract: Background: The B-cell translocation gene 2 (BTG2) is considered to act as a tumour-suppressor gene because of its antiproliferative and antimigratory activities. Higher levels of BTG2 expression in tumour cells have been linked to a better clinical outcome for several cancer entities. Here, we investigated the expression and function of BTG2 in bladder cancer. Methods: The expression of BTG2 in bladder cancer cells was silenced by RNA interference. Cell motility was investigated by wound healing and Boyden chamber assays. The protein expression of BTG2 in bladder cancer was studied by immunohistochemistry. Results: We observed that targeted suppression of BTG2 by RNA interference did not result in growth stimulation but led to a substantial inhibition of bladder cancer cell motility. Tissue microarray analyses of bladder cancer cystectomy specimens revealed that higher BTG2 expression levels within the tumours correlated strongly with a decreased cancer-specific survival for bladder cancer patients. Conclusion: These results indicate that endogenous BTG2 expression contributes to the migratory potential of bladder cancer cells. Moreover, high levels of BTG2 in bladder cancers are linked to decreased cancer-specific survival. These findings question the conception that BTG2 generally acts as a tumour suppressor and typically represents a favourable clinical marker for cancer patients.
    Type of Publication: Journal article published
    PubMed ID: 23299537
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  • 8
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; VIVO ; GENE ; GENES ; PROTEIN ; PROTEINS ; RNA ; RELEASE ; ACTIVATION ; cell cycle ; CELL-CYCLE ; E7 ; papillomavirus ; BREAST-CANCER ; TARGET ; virus ; LESIONS ; PROGRESSION ; resistance ; cervical cancer ; CERVICAL-CANCER ; PROSTATE-CANCER ; human papillomavirus ; TYPE-16 ; CANCER-CELLS ; HPV ; E6 ; ONCOGENE ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; PHENOTYPE ; ONCOPROTEIN ; METHYLTRANSFERASE ACTIVITY ; E6 ONCOPROTEIN ; ONCOLOGY ; ENHANCER ; RE ; INTERFERENCE ; RNA INTERFERENCE ; LEVEL ; USA ; oncogenes ; cancer research ; viral ; transformed cell ; GROUP PROTEIN EZH2 ; POLYCOMB REPRESSION
    Abstract: The malignant phenotype of human papillomavirus (HPV)-positive cancer cells is maintained by the activity of the viral E6 and E7 genes. Here, we identified the polycomb group gene enhancer of zeste homologue 2 (EZH2) as a novel downstream target for the viral oncogenes in HPV transformed cells. EZH2 expression was activated by HPV16 E7 at the transcriptional level via E7-mediated release of E2F from pocket proteins. RNA interference analyses showed that continuous EZH2 expression is required for the proliferation of HPV-positive tumor cells by stimulating cell cycle progression at the G(1)-S boundary. In addition to its growth-promoting activity, EZH2 also contributed to the apoptotic resistance of cervical cancer cells. Furthermore, we found that HPV-positive dysplastic and tumorigenic cervical lesions were characterized by high levels of EZH2 protein in vivo. We conclude that the E7 target gene EZH2 is a major determinant for the proliferation of HPV-positive cancer cells and contributes to their apoptotic resistance. Moreover, EZH2 may serve as a novel therapeutic target for the treatment of cervical cancer. [Cancer Res 2008;68(23):9964-72]
    Type of Publication: Journal article published
    PubMed ID: 19047178
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  • 9
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; CELL ; Germany ; INHIBITION ; THERAPY ; PROTEIN ; BINDING ; papillomavirus ; FORM ; IDENTIFICATION ; genetics ; cervical cancer ; CERVICAL-CANCER ; p53 ; human papillomavirus ; CERVICAL-CARCINOMA CELLS ; E6 ; DEGRADATION ; POSITIVE CANCER-CELLS ; AFFINITY ; VARIANT ; THERAPIES ; cancer therapy ; LIBRARIES ; TYPE-16 E6 ; development ; P53 ACTIVITY ; oncogenes ; E6-AP
    Abstract: Specific types of human papillomaviruses (HPVs) cause cervical cancer. The viral E6 oncogene is a critical factor for maintaining the malignant phenotype of HPV-positive tumour cells. By yeast two-hybrid screening of a randomised peptide expression library, we isolated linear short peptides, which specifically bind to the HPV16 E6 oncoprotein. Sequence alignments and mutational analyses of the peptides identified a hitherto undiscovered E6-binding motif. Intracellular expression of a peptide containing the novel E6-binding motif resulted in inhibition of colony formation capacity, specifically of HPV16-positive cancer cells. A solubility-optimised variant of the peptide was created, which binds to HPV16 E6 with high affinity. Its intracellular expression efficiently induced apoptosis in HPV16-positive cancer cells. This was linked to restoration of intracellular p53 activities. Thus, this newly identified E6-binding motif could form a novel basis for the development of rational strategies for the treatment of HPV16-positive preneoplastic and neoplastic lesions
    Type of Publication: Journal article published
    PubMed ID: 19099279
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