Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2

BACKGROUND: The p53 transcription factor is located at the core of a complex wiring of signaling pathways that are critical for the preservation of cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). However, relatively little is known about the role that lincRNAs play in this pathway. RESULTS: Here we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pint is a ubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, Pint promotes cell proliferation and survival by regulating the expression of genes of the TGF-β, MAPK and p53 pathways. Pint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Furthermore, Pint functional activity is highly dependent on PRC2 expression. We have also identified Pint human ortholog (PINT), which presents suggestive analogies with the murine lincRNA. PINT is similarly regulated by p53, and its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, PINT is downregulated in colon primary tumors, while its overexpression inhibits the proliferation of tumor cells, suggesting a possible role as tumor suppressor. CONCLUSIONS: Our results reveal a p53 autoregulatory negative mechanism where a lincRNA connects p53 activation with epigenetic silencing by PRC2. Additionally, we show analogies and differences between the murine and human orthologs, identifying a novel tumor suppressor candidate lincRNA.

Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.

Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2

BACKGROUND: The p53 transcription factor is located at the core of a complex wiring of signaling pathways that are critical for the preservation of cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). However, relatively little is known about the role that lincRNAs play in this pathway. RESULTS: Here we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pint is a ubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, Pint promotes cell proliferation and survival by regulating the expression of genes of the TGF-β, MAPK and p53 pathways. Pint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Furthermore, Pint functional activity is highly dependent on PRC2 expression. We have also identified Pint human ortholog (PINT), which presents suggestive analogies with the murine lincRNA. PINT is similarly regulated by p53, and its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, PINT is downregulated in colon primary tumors, while its overexpression inhibits the proliferation of tumor cells, suggesting a possible role as tumor suppressor. CONCLUSIONS: Our results reveal a p53 autoregulatory negative mechanism where a lincRNA connects p53 activation with epigenetic silencing by PRC2. Additionally, we show analogies and differences between the murine and human orthologs, identifying a novel tumor suppressor candidate lincRNA.

Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.

Multiple Myeloma with primary manifestation in the mandible: a case report

Multiple myeloma is a monoclonal malignant proliferation of plasma cells that causes osteolytic lesions in the vertebrae, ribs, pelvic bone, skull and jaw. We report on a clinical case of an 81-year-old male patient who presented with a tumefaction in the mandibular symphysis region, which had evolved over the previous seven months. In the radiographic examination, an extensive osteolytic lesion was observed in the region mentioned above. An incisional biopsy was performed and a histopathological study revealed a malignant hematopoietic neoplasm formed by plasmacytoid cells. During the bone gammagraphy a dissemination of the disease was detected in the scapula, clavicle and ribs. The diagnosis was multiple myeloma. Knowledge about the maxillofacial manifestations of multiple myeloma is important for the early diagnosis of the disease, since its primary form can manifest itself in the jaw. In the clinical case presented here, we highlight the interdisciplinarity needed to obtain a diagnosis and treatment of multiple myeloma

Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design

INTRODUCTION: We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. METHODS: Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. DISCUSSION: This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain.

Estimating Gross Value Added (GVA) across multiple scales: theoretical approach and empirical validation

This paper presents an application of the Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MuSIASEM) approach to the estimation of quantities of Gross Value Added (GVA) referring to economic entities defined at different scales of study. The method first estimates benchmark values of the pace of GVA generation per hour of labour across economic sectors. These values are estimated as intensive variables –e.g. €/hour– by dividing the various sectorial GVA of the country (expressed in € per year) by the hours of paid work in that same sector per year. This assessment is obtained using data referring to national statistics (top down information referring to the national level). Then, the approach uses bottom-up information (the number of hours of paid work in the various economic sectors of an economic entity –e.g. a city or a province– operating within the country) to estimate the amount of GVA produced by that entity. This estimate is obtained by multiplying the number of hours of work in each sector in the economic entity by the benchmark value of GVA generation per hour of work of that particular sector (national average). This method is applied and tested on two different socio-economic systems: (i) Catalonia (considered level n) and Barcelona (considered level n-1); and (ii) the region of Lima (considered level n) and Lima Metropolitan Area (considered level n-1). In both cases, the GVA per year of the local economic entity –Barcelona and Lima Metropolitan Area – is estimated and the resulting value is compared with GVA data provided by statistical offices. The empirical analysis seems to validate the approach, even though the case of Lima Metropolitan Area indicates a need for additional care when dealing with the estimate of GVA in primary sectors (agriculture and mining).

Ischemic heart disease and primary care: identifying gender-related differences. An observational study

Background: Gender-related differences are seen in multiple aspects of both health and illness. Ischemic heart disease (IHD) is a pathology in which diagnostic, treatment and prognostic differences are seen between sexes, especially in the acute phase and in the hospital setting. The objective of the present study is to analyze whether there are differences between men and women when examining associated cardiovascular risk factors and secondary pharmacological prevention in the primary care setting. Methods: Retrospective descriptive observational study from January to December of 2006, including 1907 patients diagnosed with ischemic heart disease in the city of Lleida, Spain. The clinical data were obtained from computerized medical records and pharmaceutical records of medications dispensed in pharmacies with official prescriptions. Data was analyzed using bivariate descriptive statistical analysis as well as logistic regression. Results: There were no gender-related differences in screening percentages for arterial hypertension, diabetes, obesity, dyslipemia, and smoking. A greater percentage of women were hypertensive, obese and diabetic compared to men. However, men showed a tendency to achieve control targets more easily than women, with no statistically significant differences. In both sexes cardiovascular risk factors control was inadequate, between 10 and 50%. For secondary pharmaceutical prevention, the percentages of prescriptions were greater in men for anticoagulants, beta-blockers, lipid-lowering agents and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, with age group variations up to 10%. When adjusting by age and specific diagnoses, differences were maintained for anticoagulants and lipid-lowering agents. Conclusion: Screening of cardiovascular risk factors was similar in men and women with IHD. Although a greater percentage of women were hypertensive, diabetic or obese, their management of risk factors tended to be worse than men. Overall, a poor control of cardiovascular risk factors was noted. Taken as a whole, more men were prescribed secondary prevention drugs, with differences varying by age group and IHD diagnosis.

Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data

Background: We use an approach based on Factor Analysis to analyze datasets generated for transcriptional profiling. The method groups samples into biologically relevant categories, and enables the identification of genes and pathways most significantly associated to each phenotypic group, while allowing for the participation of a given gene in more than one cluster. Genes assigned to each cluster are used for the detection of pathways predominantly activated in that cluster by finding statistically significant associated GO terms. We tested the approach with a published dataset of microarray experiments in yeast. Upon validation with the yeast dataset, we applied the technique to a prostate cancer dataset. Results: Two major pathways are shown to be activated in organ-confined, non-metastatic prostate cancer: those regulated by the androgen receptor and by receptor tyrosine kinases. A number of gene markers (HER3, IQGAP2 and POR1) highlighted by the software and related to the later pathway have been validated experimentally a posteriori on independent samples. Conclusion: Using a new microarray analysis tool followed by a posteriori experimental validation of the results, we have confirmed several putative markers of malignancy associated with peptide growth factor signalling in prostate cancer and revealed others, most notably ERRB3 (HER3). Our study suggest that, in primary prostate cancer, HER3, together or not with HER4, rather than in receptor complexes involving HER2, could play an important role in the biology of these tumors. These results provide new evidence for the role of receptor tyrosine kinases in the establishment and progression of prostate cancer.