Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long non-coding RNAs (lncRNAs) as crucial determinants of HCC development. In this study, we report the lncRNA HOTTIP as significantly up-regulated in HCC specimens. HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression via interaction with the WDR5 / MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinico-pathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients’ clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data are obtained from snap-frozen needle HCC biopsies (n=52) matched with their non-neoplastic counterparts collected from patients that had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP / HOXA13. Conclusion: our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression to metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis and paves the way for further investigation about the possible role of HOTTIP as predictive biomarker of HCC.
The applied procedures may be helpful for multi-centre focus group research on other topics.
The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankyloblepharon ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary keratinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the ΔNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasomemediated ΔNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, thereby limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation-differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.
A great deal of attention has been focused on adverse effects of tobacco smoking on conception, pregnancy, fetal, and child health. The aim of this paper is to discuss the current evidence regarding short and long-term health effects on child health of parental smoking during pregnancy and lactation and the potential underlying mechanisms. Studies were searched on MEDLINE® and Cochrane database inserting, individually and using the Boolean ANDs and ORs, ‘pregnancy’, ‘human lactation’, ‘fetal growth’, ‘metabolic outcomes’, ‘obesity’, ‘cardiovascular outcomes’, ‘blood pressure’, ‘brain development’, ‘respiratory outcomes’, ‘maternal or paternal or parental tobacco smoking’, ‘nicotine’. Publications coming from the reference list of studies were also considered from MEDLINE. All sources were retrieved between 2015-01-03 and 2015-31-05. There is overall consistency in literature about negative effects of fetal and postnatal exposure to parental tobacco smoking on several outcomes: preterm birth, fetal growth restriction, low birth weight, sudden infant death syndrome, neurodevelopmental and behavioral problems, obesity, hypertension, type 2 diabetes, impaired lung function, asthma and wheezing. While maternal smoking during pregnancy plays a major role on adverse postnatal outcomes, it may also cumulate negatively with smoking during lactation and with second-hand smoking exposure. Although this review was not strictly designed as a systematic review and the PRISMA Statement was not fully applied it may benefit the reader with a promptly and friendly readable update of the matter. This review strengthens the need to plan population health policies aimed to implement educational programs to hopefully minimize tobacco smoke exposure during pregnancy and lactation.
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