Regulation of p63 Isoforms by Snail and Slug Transcription Factors in Human Squamous Cell Carcinoma.
Herfs, Michael ; Hubert, Pascale ; Suarez-Carmona, Meggy et al
in American Journal of Pathology (2010), 176(4), 1941-1949
TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the ... [more ▼]
TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the expression of p63 is required for proper development of epithelial structures, the role of p63 in tumorigenesis remains unclear. Here, we investigated the role of Snail and Slug transcription factors, known to promote epithelial-to-mesenchymal transitions during development and cancer, in the regulation of p63 isoforms in human squamous cell carcinoma (SCC). In the present study, we observed that the expressions of DeltaN and TAp63 isoforms were, respectively, down- and up-regulated by both Snail and Slug. However, the induction of TAp63 was not directly caused by these two transcription factors but resulted from the loss of DeltaNp63, which acts as dominant-negative inhibitor of TAp63. In SCC cell lines and cancer tissues, high expression of Snail and Slug was also significantly associated with altered p63 expression. Finally, we showed that DeltaNp63 silencing reduced cell-cell adhesion and increased the migratory properties of cancer cells. These data suggest that the disruption of p63 expression induced by Snail and Slug plays a crucial role in tumor progression. Therefore, p63 and its regulating factors could constitute novel prognosis markers in patients with SCC and attractive targets for the therapeutic modulation of neoplastic cell invasiveness. [less ▲]Detailed reference viewed: 79 (18 ULg)
Implication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia
Demoulin, Stéphanie ; Somja, Joan ; Herfs, Michael et al
Poster (2010)Detailed reference viewed: 9 (0 ULg)
Fish and chips
DELVENNE, Philippe ; Deprez, Manuel ; BISIG, Bettina et al
in Revue Médicale de Liège (2010), 65 Spec no.
Academic hospital laboratories should offer patients the possibility to have the most accurate diagnosis by the development of new analyses, such as molecular biology tests including FISH (Fluorescent In ... [more ▼]
Academic hospital laboratories should offer patients the possibility to have the most accurate diagnosis by the development of new analyses, such as molecular biology tests including FISH (Fluorescent In Situ Hybridization) and chips (microarrays,...). The purpose of this article is to describe the principles and the potential applications of these techniques. [less ▲]Detailed reference viewed: 51 (9 ULg)
Local applications of GM-CSF induce the recruitment of immune cells in cervical low-grade squamous intraepithelial lesions.
Hubert, Pascale ; Doyen, Jean ; Capelle, Xavier et al
in American Journal of Reproductive Immunology (2010), 64(2), 126-136
Abstract Problem Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished ... [more ▼]
Abstract Problem Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished capacity to capture viral antigens and to induce a protective immune response. Method of study To test if a cervical application of GM-CSF could restore an immune response against HPV in women with cervical low-grade squamous intraepithelial lesions (LSIL). We performed two clinical trials with11 healthy women and 15 patients with LSIL. Results GM-CSF applications were well tolerated in all enrolled women and no difference in toxicity between the treated and placebo groups was observed during the follow up (until 30 months). Interestingly, in the GM-CSF treated group, a significant increased APC and cytotoxic T lymphocyte infiltration was observed in the cervical biopsies with no change in regulatory T cell numbers. All the HPV16+ patients exhibited an immune response against HPV16 after GM-CSF applications, as shown by NK and/or T cells producing IFN-γ whereas no cellular immune response was observed before the treatment. Moreover, the anti-VLP antibody titers also increased after the treatment. Conclusion These encouraging results obtained from a limited number of subjects justify further study on the therapeutic effect of APC in cervical (pre)neoplastic lesions. [less ▲]Detailed reference viewed: 133 (53 ULg)
Effects of HPV-16 E5, E6 and E7 Proteins on Survival, Adhesion, Migration and Invasion of Trophoblastic Cells
; ; et al
in Carcinogenesis (2010), 31(3), 473-80
Amongst high-risk human papillomaviruses (HPV), HPV-16 infection is the most prevalent causative factor for cervical cancer. Beside other mucosal targets, HPV-16 was reported to infect the placenta and to ... [more ▼]
Amongst high-risk human papillomaviruses (HPV), HPV-16 infection is the most prevalent causative factor for cervical cancer. Beside other mucosal targets, HPV-16 was reported to infect the placenta and to replicate in trophoblastic cells. Since these cells share invasive properties of tumoral cells, they represent an ideal model to investigate several oncogenic processes. In the present work, we analyzed the impacts of HPV-16 E5, E6 and E7 oncoproteins on the trophoblastic model. Our results showed that E5 impaired the viability of trophoblastic and cervical cell lines but E6 and E7, favouring cell growth, neutralised the E5 cytotoxic effect. In addition, E5 decreased the adhesiveness of trophoblastic cells to the tissue culture plastic and to endometrial cells similarly as previously described for E6 and E7. E5 and E6 plus E7 increased also their migration and their invasive properties. Cells expressing HPV-16 early proteins under the control of the LCR endogenous promoter displayed growth advantage and were also more motile and invasive compared to control cells. Interestingly, the E-cadherin was down regulated in trophoblastic cells expressing E5, E6 and E7. NF-kB and AP-1 activities were also enhanced. In conclusion, HPV-16 early proteins enhanced trophoblastic growth and intensify the malignant phenotype by impairing cell adhesion leading to increased cellular motile and invasive properties. HPV-16 E5 participated, with E6 and E7, in these changes by impairing Ecadherin expression, a hallmark of malignant progression. [less ▲]Detailed reference viewed: 68 (6 ULg)
Progression model tissue microarray (TMA) for the study of uterine carcinomas.
; Boniver, Jacques ; Delvenne, Philippe
in Disease Markers (2010), 28(5), 267-72
Cervical and endometrial uterine carcinomas are heterogeneous groups of cancers, which are preceded by preneoplastic lesions. More accurate tools are needed to improve the diagnosis and to define markers ... [more ▼]
Cervical and endometrial uterine carcinomas are heterogeneous groups of cancers, which are preceded by preneoplastic lesions. More accurate tools are needed to improve the diagnosis and to define markers which may be relevant for the diagnosis, prediction of disease progression and therapeutic response.High throughput technologies for testing and validating molecular targets in cancer lesions and in their precursors are presently available. Among them, the tissue microarray (TMA) presents the advantage of a morphological control of the analyzed tissue fragment. In this article, we review the different aspects of the TMA technology with a special consideration to a uterine carcinogenesis model. [less ▲]Detailed reference viewed: 11 (3 ULg)
Current concepts in the pathology and epigenetics of endometrial carcinoma.
; Somja, Joan ; Dehan, Pierre et al
in Pathology (2010), 42(7), 613-7
In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and is the fourth most common cancer in women. Two different clinicopathological subtypes are ... [more ▼]
In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and is the fourth most common cancer in women. Two different clinicopathological subtypes are recognised: the oestrogen-related (type I, endometrioid) and the non-oestrogen related (type II, non-endometrioid). This article reviews the epidemiology, risk factors, genetic alterations during endometrial carcinogenesis, features of tumours and precursors and early detection of the disease. Insights into the epigenetic alterations, with emphasis on DNA methylation during endometrial carcinogenesis, and their diagnostic value are also provided. [less ▲]Detailed reference viewed: 57 (10 ULg)
Increase in viral load, viral integration, and gain of telomerase genes during uterine cervical carcinogenesis can be simultaneously assessed by the HPV 16/18 MLPA-assay.
; ; Herfs, Michael et al
in American Journal of Pathology (2010), 177(4), 2022-33
Oncogenic human papillomavirus (HPV) infection is the most important risk factor in cervical carcinogenesis cases; high viral loads, viral integration into the host genome, and gain of the telomerase ... [more ▼]
Oncogenic human papillomavirus (HPV) infection is the most important risk factor in cervical carcinogenesis cases; high viral loads, viral integration into the host genome, and gain of the telomerase-related genes, TERT and TERC, are all factors associated with progression to cancer. A recently developed multiparameter HPV 16/18 multiplex ligation-dependent probe amplification (MLPA) assay, which allows the simultaneous assessment of these factors, was applied to a series of 67 normal and (pre)malignant frozen uterine cervical samples, as well as to 91 cytological preparations, to test the ability of the MLPA assay to identify high-risk lesions on the basis of these factors. Validation was performed using quantitative PCR, the PapilloCheck and fluorescence in situ hybridization. Only 5 out of 37 normal tissue samples or low-grade cervical lesions (ie, CIN1 and condyloma) showed either an HPV16 viral load higher than 25 copies per cell, viral integration, and/or gain of one of the telomerase-related genes, whereas for the high-grade cervical lesions, one or more of these risk factors was found in 25 of 30 cases. The HPV MLPA assay showed a sensitivity of 83% and a specificity of 86% in frozen cervical specimens. Furthermore, the feasibility of the MLPA assay was shown for cytological samples, where in 57% of high-grade squamous intraepithelial lesion cases, the high-risk factors were detected using this assay. [less ▲]Detailed reference viewed: 19 (3 ULg)
The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context.
Herman, Ludivine ; Hubert, Pascale ; Herfs, Michael et al
in European Journal of Immunology (2010), 40(11), 3075-84
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately ... [more ▼]
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-kappaB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE(2)), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells. [less ▲]Detailed reference viewed: 32 (10 ULg)
Characterization of hepatitis C virus-induced nasal mucosa remodelling.
El Shazly, Amr ; ; Roncarati, Patrick et al
in Histopathology (2010), 57(3), 488-92Detailed reference viewed: 24 (4 ULg)
Human Papillomavirus Virus-Like particles and NK cell interactions:role of CD16
Renoux, Virginie ; ; et al
in International Immunology (2010), 22(suppl Pt 5), 17Detailed reference viewed: 38 (13 ULg)
Regulation of the Immune Response by Innate Lymphocyte and Dendritic Cell Cross Talk
Reschner, Anca ; Langers, Inge ; Renoux, Virginie et al
in Welles, Lorraine (Ed.) Dendritic Cells: Types, Life Cycles and Biological Functions (2010)
Dendritic cell (DC) is the generic name of different professional antigen presenting cell sub-populations, which are responsible for the initiation of specific immune responses. Recently, DC have been ... [more ▼]
Dendritic cell (DC) is the generic name of different professional antigen presenting cell sub-populations, which are responsible for the initiation of specific immune responses. Recently, DC have been involved in supporting innate immunity by interacting with various innate lymphocytes, such as natural killer (NK), NKT or γδ T (T cells expressing γδ T cell receptor). The functional links between innate lymphocytes and DC have been investigated widely and different studies demonstrated that the cross-talk between innate lymphocytes and DC was found to be multi-directional, involving not only cell-cell contacts but also soluble factors which lead to lymphocyte activation and DC maturation. The final outcome of these cellular interactions may have a dramatic impact on the quality and strength of the down-stream immune responses, mainly in the context of early responses to tumor cells and infectious agents. Interestingly, DC, NK and γδ T cells also share similar functions, such as antigen uptake and presentation, as well as cytotoxic and tumoricidal activity. In addition, NK and NKT cells have the ability to kill DC. This chapter will focus upon the different aspects of the cross-talk between DC and innate lymphocytes and its key role in all the steps of the immune response. These cellular interactions may be particularly critical in situations where immune surveillance requires efficient early innate responses. [less ▲]Detailed reference viewed: 82 (26 ULg)
Influence of the vaccine agent of uterine cervical cancer on the crosstalk between Natural Killer and Dendritic Cells
Renoux, Virginie ; Langers, Inge ; Reschner, Anca et al
Poster (2009, November)Detailed reference viewed: 39 (18 ULg)
Epithelial metaplasia: adult stem cell reprogramming and (pre)neoplastic transformation mediated by inflammation?
Herfs, Michael ; Hubert, Pascale ; Delvenne, Philippe
in Trends in Molecular Medicine (2009), 15(6), 245-253Detailed reference viewed: 192 (15 ULg)
High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells
Herfs, Michael ; Herman, Ludivine ; Hubert, Pascale et al
in Cancer Immunology, Immunotherapy (2009), 58(4), 603-614Detailed reference viewed: 54 (18 ULg)
Surface Mucin-1 does not play a role in dendritic cell migration
; Caberg, Jean-Hubert ; et al
in Molecular Immunology (2009), 46(4), 738-742Detailed reference viewed: 29 (3 ULg)
Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20
Caberg, Jean-Hubert ; Hubert, Pascale ; Herman, Ludivine et al
in Cancer Immunology, Immunotherapy (2009), 58(1), 39-47Detailed reference viewed: 72 (7 ULg)
DNA methylation and cancer diagnosis: new methods and applications.
Dehan, Pierre ; Kustermans, Gaëlle ; Guénin, Samuel et al
in Expert Review of Molecular Diagnostics (2009), 9(7), 651-7
Methylation of cytosines in cytosine-guanine (CpG) dinucleotides is one of the most important epigenetic alterations in animals. The presence of methylcytosine in the promoter of specific genes has ... [more ▼]
Methylation of cytosines in cytosine-guanine (CpG) dinucleotides is one of the most important epigenetic alterations in animals. The presence of methylcytosine in the promoter of specific genes has profound consequences on local chromatin structure and on the regulation of gene expression. Changes in DNA methylation play a central role in carcinogenesis. Hypermethylation and consecutive transcriptional silencing of tumor-suppressor genes has been documented in numerous cancers. The identification of target genes silenced by this modification has a great impact on diagnosis, classification, definition of risk groups and prognosis of cancer patients. Here we outline genome-wide techniques aiming at the identification of relevant methylated promoters. Methods and applications allowing clinicians to monitor the methylation of target genes will be also reviewed. [less ▲]Detailed reference viewed: 86 (17 ULg)
Belgian consensus guidelines for follow-up of women with cervical cytological abnormalities.
; ; et al
in Acta Clinica Belgica (2009), 64(2), 136-43Detailed reference viewed: 94 (11 ULg)
Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma.
Vandermeers, Fabian ; Hubert, Pascale ; Delvenne, Philippe et al
in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2009), 15(8), 2818-28
PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to ... [more ▼]
PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and RESULTS: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patient's biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. CONCLUSIONS: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma. [less ▲]Detailed reference viewed: 61 (11 ULg)