Epigenetics of cervical cancer. An overview and therapeutic perspectives

Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis

Coastal erosion and beach stability in Limón, Caribbean Sea, Costa Rica

Correo electrónico investigador: [email protected] estudió la variación de la línea de costa en algunas playas del Caribe de Costa Rica. Para Moín se evaluó la variación de la línea de costa desde las primeras fotografías aéreas (1952), para antes y después del levantamiento tectónico que produjo el terremoto de abril de 1991. Procesos de erosión y acreción se han dado en esta zona producto de no solo de tectonismo, sino también la construcción de estructuras portuarias. Se ajustaron perfiles parabólicos a la línea de costa para evaluar el equilibrio estático de la playa de Moín y la relación que tiene esta con el cambio del patrón de oleaje debido al levantamiento de la Isla Pájaros antes y después del terremoto y de la influencia de la construcción de las terminales portuarias. Este ajuste parabólico se extendió a otras playas de Limón para evaluar también su estado de equilibrio. Parámetros físicos como temperatura superficial del mar, altura de ola y nivel del mar, fueron evaluados para relacionar con los procesos de erosión que experimenta en la región. Los resultados indican que tanto un aumento en la temperatura del mar y el nivel del mar, con un proceso tectónico aún activo y fenómenos océano-meteorológicos extremos en los últimos años, podrían justificar la erosión evidente que continua en la zona.The variation of the coastline was studied in some beaches of the Caribbean of Costa Rica. For Moín, the variation of the coastline was evaluated since the first aerial photographs (1952), before and after the tectonic uplift that produced the April 1991 earthquake. Erosion and accretion processes have occurred in this area as a result of not only tectonism, but also the construction of port structures. Parabolic profiles were adjusted to the coastline to evaluate the static equilibrium of the Moín beach and its relationship with the change in the wave pattern due to the rise of Pájaros Island before and after the earthquake and the influence of the construction of port terminals. This parabolic adjustment was extended to other beaches in Limón to also assess its state of equilibrium. Physical parameters such as sea surface temperature, wave height and sea level were evaluated to relate the erosion processes experienced in the region. The results indicate that both an increase in sea temperature and sea level, with a tectonic process still active and extreme ocean-meteorological phenomena in recent years, could justify the evident erosion that continues in the area.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Ciencias del Mar y Limnología (CIMAR)UCR::Vicerrectoría de Docencia::Ciencias Sociales::Facultad de Ciencias Sociales::Escuela de GeografíaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigaciones Geofísicas (CIGEFI

Modulating epigenetic modifications for cancer therapy (Review)

Cancer is a global public health concern. Alterations in epigenetic processes are among the earliest genomic aber- rations occurring during cancer development and are closely related to progression. Unlike genetic mutations, aberrations in epigenetic processes are reversible, which opens the possi- bility for novel pharmacological treatments. Non-coding RNAs (ncRNAs) represent an essential epigenetic mechanism, and emerging evidence links ncRNAs to carcinogenesis. Epigenetic drugs (epidrugs) are a group of promising target therapies for cancer treatment acting as coadjuvants to reverse drug resis- tance in cancer. The present review describes central epigenetic aberrations during malignant transformation and explains how epidrugs target DNA methylation, histone modifications and ncRNAs. Furthermore, clinical trials focused on evaluating the effect of these epidrugs alone or in combination with other anticancer therapies and other ncRNA-based therapies are discussed. The use of epidrugs promises to be an effective tool for reversing drug resistance in some patients with cancer.</p

The effects of DNA methylation and histone deacetylase inhibitors upon the human papillomavirus early genes expression in cervical cancer. An in vitro and clinical study

BACKGROUND: The methylation status at the human papilloma virus (HPV) genome found in pre-invasive and invasive cervical lesions suggests that neoplastic transformation can be suppressed by gene hypermethylation, whereas hypomethylation accompanies or causes cancer progression; hence, epigenetic therapy aimed at reactivating cellular suppressor-gene expression has the potential to act as a tumor promoter by enhancing HPV oncoprotein expression in HPV-related malignancies. The objective of this study was to determine the influence of hydralazine and valproate on HPV oncogene expression in cervical cancer cell lines and the primary tumors of patients undergoing treatment with hydralazine and valproate. RESULTS: Overall, hydralazine and valproate either alone or combined exerted a growth inhibitory effect on cervical cancer cell lines. A cell line-specific up-regulating effect was observed on E6/E7 gene expression, which in general correlated with DNA hypomethylation and histone acetylation at the long control region (LCR). Nonetheless, E6/E7 expression was unchanged or decreased in the majority of patients with cervical cancer treated with hydralazine, valproate, or both. In some cervical cancer cell lines, these drugs led to increased transcription of p53, and increased its stabilization due to acetylation at lysines 273 and 282, which allowed a higher bax-protein transactivating effect. CONCLUSION: The results of this study demonstrate that hydralazine and valproate can be safely administered to HPV-related malignancies such as cervical cancer because they do not increase viral oncoprotein expression. Most importantly, the antitumor effect of hydralazine and valproate in cervical cancer may at least partially depend on an up-regulating effect on p53 gene and on the valproate-induced hyperacetylation of p53 protein, protecting it from degradation by E6

Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways

A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells

Gene expression profiles induced by E6 from non-European HPV18 variants reveals a differential activation on cellular processes driving to carcinogenesis

AbstractCervical cancer in developed countries remains as a major concern on public health policies due to incidence and mortality rates. Persistent infection with high risk human papillomavirus is a necessary etiological agent in the progression to invasive cervical carcinoma. A proposed hypothesis is the association between more aggressive HPV variants and the risk to develop cervical cancer. In order to have a global perspective in terms of cellular transcripts and molecular pathways affected by HPV18 E6 intratype variants; we conducted a genome wide analysis of gene expression. Our results show that E6 derived from non-European variants are able to up-regulate cellular transcripts associated to the hallmarks of cancer; such as cell cycle, migration, Wnt pathway and mTor signaling. Moreover, we were able to show that HPV18 E6 from African variant had a major effect on cellular processes such as cell cycle and migration as confirmed by functional studies

Low endemicity and low pathogenicity of rotaviruses among rural children in Costa Rica

Artículo científico -- Universidad de Costa Rica. Instituto de Investigaciones en Salud. 1985Rotaviruses were prospectively studied in 51 rural Costa Rican children from birth to two years. Samples of feces were collected weekly over a 33-month period. Rotavirus was detected in 45 (1.04%) of 4,317 fecal specimens; 39 infections were documented (an incidence of 0.5 infection per child-year), only five of which were associated with diarrhea (a pathogenicity of 12.8%). Secretory antibody in fecal extracts, detected in six of 39 infections, was short lived and did not protect against reinfection. Serum antibody was present in 69.6% of two-year-old children, but was not detected in 18.8% with documented infections. On the other hand, serum antibody was present in six of 14 children in whom rotavirus was not detected, thus increasing the overall incidence to 0.6 infection per child-year. The combination of prolonged breast-feeding, exposure to a lower infecting dose (compared with urban children), and a higher standard of hygiene than expected may explain the low incidence and low pathogenicity of rotavirus among these rural children.Universidad de Costa Rica. Instituto de Investigaciones en Salud.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA