Special Issue: "Role of MicroRNA in Cancer Development and Treatment"

Exposure to environmental contaminants may lead to changes in the expression of microRNAs (miRNAs), resulting in several health effects [...]

Physical activity and cancer prevention: a review of current evidence and biological mechanisms

Objective. The main aim of this paper is to review the evidence available from the date of PubMed?s inception to May 2011 for a link between cancer and physical activity (PA) in both animal models and humans. Methods. We decided to select studies that comply with the scheme proposed by the American College of Sports Medicine/ American Heart Association (ACSM/AHA) that distinguish occupational physical activity (OPA) and leisure-time physical activity (LT-PA), further classified in three levels of intensity (low, moderate and heavy) based on the Metabolic Equivalent of Task (MET) index. Results. Considering animal models, there was strong evidence for an inverse association between voluntary wheel exercise and the risk of colon and breast cancer. Regarding human studies, we identified the following main results: 1) colorectum: LT-PA provided an overall colon risk reduction of 13-14%; 2) breast: significant reduction in the frequency of post-menopausal (PMP) cancers in women that practiced heavy and moderate LT-PA; 3) prostate: heavy OPA and LT-PA seemed to reduce the risk of advanced prostate cancers; 4) endometrium: strong protective effect of heavy/moderate LT-PA among overweight/ obese women; 5) lung: inverse relationship between heavy LT-PA and lung cancer in former or current smokers across all histologies. Conclusion. Increased LT-PA is associated with cancer prevention in several organs, but strong biases, such as body mass index (BMI), gender and age, make it difficult to assess which aspects of PA contribute most strongly to the reduced risk. Furthermore, we found few studies that indicated a protective role for OPA in cancer prevention when compared with LT-PA

Small RNAs in eucaryotes: new clues for amplifying microRNA benefits

miRNAs, the smallest nucleotide molecules able to regulate gene expression at post transcriptional level, are found in both animals and plants being involved in fundamental processes for growth and development of living organisms. The number of miRNAs has been hypothesized to increase when some organisms specialized the process of mastication and grinding of food. Further to the vertical transmission, miRNAs can undergo horizontal transmission among different species, in particular between plants and animals. In the last years, an increasing number of studies reported that miRNA passage occurs through feeding, and that in animals, plant miRNAs can survive the gastro intestinal digestion and transferred by blood into host cells, where they can exert their functions modulating gene expression. The present review reports studies on miRNAs during evolution, with particular focus on biogenesis and mechanisms regulating their stability in plants and animals. The different biogenesis and post biogenesis modifications allow to discriminate miRNAs of plant origin from those of animal origin, and make it possible to better clarify the controversial question on whether a possible cross-kingdom miRNA transfer through food does exist. The majority of human medicines and supplements derive from plants and a regular consumption of plant food is suggested for their beneficial effects in the prevention of metabolic diseases, cancers, and dietary related disorders. So far, these beneficial effects have been generally attributed to the content of secondary metabolites, whereas mechanisms regarding other components remain unclear. Therefore, in light of the above reported studies miRNAs could result another component for the medical properties of plants. miRNAs have been mainly studied in mammals characterizing their sequences and molecular targets as available in public databases. The herein presented studies provide evidences that miRNA situation is much more complex than the static situation reported in databases. Indeed, miRNAs may have redundant activities, variable sequences, different methods of biogenesis, and may be differently influenced by external and environmental factors. In-depth knowledge of mechanisms of synthesis, regulation and transfer of plant miRNAs to other species can open new frontiers in the therapy of many human diseases, including cancer

MiR\u201119 in blood plasma reflects lung cancer occurrence but is not specifically associated with radon exposure

Radon is one of the most powerful carcinogens, particularly in terms of lung cancer onset and development. miRNAs may be considered not only as markers of the ongoing tumorigenesis but also as a hallmark of exposure to radiation, including radon and its progeny. Therefore, the purpose of the present study was to estimate the value of plasma miR\u201119b\u20113p level as the prospective marker of the response to radon exposure in lung cancer pathogenesis. A total of 136 subjects were examined, including 49 radon\u2011exposed patients with lung cancer, 37 patients with lung cancer without radon exposure and 50 age/sex matched healthy controls. Total RNA from blood samples was extracted and used to detect miR\u201119b\u20113p expression via reverse transcription quantitative\u2011polymerase chain reaction. The 2\u2011\u394\u394Cqmethod was used to quantify the amount of relative miRNA. The plasma level of p53 protein was determined using a Human p53 ELISA kit. Plasma miR\u201119b\u20113p level was significantly higher in the patients with lung cancer groups, compared with the healthy control group (P<0.0001). No other statistically significant differences were determined in the expression level of plasma miR\u201119b\u20113p between patients diagnosed with lung cancer exposed to radon and not exposed to radon. The expression level of free circulating miR\u201119b\u20113p was higher in the group of non\u2011smoking patients with lung cancer, compared with smokers with lung cancer. The miR\u201119b\u20113p was 1.4\u2011fold higher in non\u2011smokers than in smokers (P<0.05). No association between plasma levels of p53 protein and miR\u201119b\u20113p freely circulating in patients with lung cancer was observed. No other statistically significant differences were determined in the plasma p53 protein level between patients diagnosed with lung cancer exposed and not exposed to radon. These results indicated that detection of miR\u201119b\u20113p levels in plasma potentially could be exploited as a noninvasive method for the lung cancer diagnostics. However, this miRNA is not suitable as the precise marker for radon impact

The Interaction among Microbiota, Epigenetic Regulation, and Air Pollutants in Disease Prevention

open6noEnvironmental pollutants can influence microbiota variety, with important implications for the general wellbeing of organisms. In subjects at high-risk of cancer, gut, and lung microbiota are distinct from those of low-risk subjects, and disease progression is associated with microbiota alterations. As with many inflammatory diseases, it is the combination of specific host and environmental factors in certain individuals that provokes disease outcomes. The microbiota metabolites influence activity of epigenetic enzymes. The knowledge of the mechanisms of action of environmental pollution now includes not only the alteration of the gut microbiota but also the interaction between different human microbiota niches such as the lung–gut axis. The epigenetic regulations can reprogram differentiated cells in response to environmental changes. The microbiota can play a major role in the progression and suppression of several epigenetic diseases. Accordingly, the maintenance of a balanced microbiota by monitoring the environmental stimuli provides a novel preventive approach for disease prevention. Metagenomics technologies can be utilized to establish new mitigation approaches for diseases induced by polluted environments. The purpose of this review is to examine the effects of particulate matter exposure on the progression of disease outcomes as related to the alterations of gut and lung microbial communities and consequent epigenetic modificationsopenAlessandra Pulliero, Deborah Traversi, Elena Franchitti, Martina Barchitta, Alberto Izzotti, Antonella AgodiPulliero, Alessandra; Traversi, Deborah; Franchitti, Elena; Barchitta, Martina; Izzotti, Alberto; Agodi, Antonell

Prediction of Titanium Implant Success by Analysis of microRNA Expression in Peri-Implant Tissue. A 5-Year Follow-Up Study

The aim of the present study is to evaluate the expression of microRNA (miRNA) in peri-implant soft tissue and to correlate epigenetic information with the clinical outcomes of the implants up to the five-year follow-up. Seven patients have been rehabilitated with fixed screw-retained bridges each supported by implants. Peri-implant bone resorption and soft tissue health parameters have been recorded over time with a five-year follow-up. Mini-invasive samples of soft peri-implant tissue have been taken three months after implant insertion. miRNA have been extracted from cells of the soft tissue samples to evaluate gene-expression at the implant sites by microarray analysis. The epigenomic data obtained by microarray technology has been statistically analyzed by dedicated software and compared with measured clinical parameters. Specific miRNA expression profiles predictive of specific clinical outcomes were found. In particular, some specific miRNA signatures appeared to be \u201cprotective\u201d from bone resorption despite the presence of plaque accumulation. miRNA may be predictors of dental implant clinical outcomes and may be used as biomarkers for diagnostic and prognostic purposes in the field of implant dentistry

TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear

In contrast to TP53, cancer development is rarely associated with mutations in the TP63 and TP73 genes. Recently, next generation sequencing analysis revealed that TP63 mutations are frequent, specifically in cutaneous melanomas. Cutaneous melanoma represents 4% of skin cancers but it is responsible for 80% of skin cancer related deaths. In the present study, we first determined whether all three members of the P53 family of transcription factors were found mutated in cutaneous melanomas by retrieving all TP53, TP63 and TP73 mutations from cBioPortal (http://www.cbioportal.org/). TP53 and TP63 were frequently mutated [15.0% (91/605) and 14.7% (89/605), respectively], while TP73 [1.5% (9/605)] was more rarely mutated (p<0.0001). A UV-mutation fingerprint was recognized for TP63 and TP73 genes. Then, we tried to evaluate the potential role of TP63 mutations as drivers or passengers in the tumorigenic process. In the former case, the amino acid substitutions should cause significant functional consequences on the main biochemical activity of the P63 protein, namely transactivation. The predicted effects of specific amino acid substitutions by two bioinformatics tools were rather different. Using a yeast-based functional assay, the observed hotspot mutant R379CP63 protein exhibited a substantial residual activity compared to the wild-type (>70%). This result does not support a major role of the mutant P63 protein in melanomagenesis while it is still consistent with the TP63 gene being a recorder of UV exposure. The TP63 mutation spectrum from cutaneous melanomas, when compared with that observed at the germinal level in patients affected by P63-associated diseases [ectodermal dysplasia syndromes, (EDs)], revealed significant differences. The TP63 mutations were more frequent at CpGs sites (p<0.0001) in EDs and at PyPy sites (p<0.0001) in cutaneous melanomas. The two spectra differed significantly (p<0.0001). We conclude that TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

Chronic inflammation plays a crucial role in the carcinogenesis process and in particular in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods

Mechanisms Of Inhibition Of Cigarette Smoke Genotoxicity And Carcinogenicity

Epidemiological studies have demonstrated that it is possible to prevent lung cancer and other smoke-related diseases by avoiding exposures to tobacco smoke. A complementary strategy is chemoprevention, which is based on the administration of dietary and pharmacological agents, which is addressed to (a) addicted active smokers, who are unable to quit smoking, (b) ex-smokers, who are still at risk for several years, and (c) involuntary smokers, including passively exposed individuals as well as transplacentally exposed individuals. The biological effects of cigarette smoke (CS) as a complex mixture, either mainstream (MCS) or sidestream (SCS) or environmental (ECS), have been poorly explored. We showed that MCS and ECS induce a broad variety of alterations of intermediate biomarkers in animal models, including adducts to nuclear DNA and mtDNA, oxidatively generated DNA damage, proliferation, apoptosis, alterations of oncogenes and tumor suppressor genes, multigene expression, microRNA and proteome profiles as well as cytogenetic damage in the respiratory tract, bone marrow and peripheral blood. CS-altered end-points were variously modulated by chemopreventive agents of natural or pharmacological origin, such as N-acetyl-L-cysteine (NAC), 1,2-dithiole-3-thione, oltipraz, 5,6-benzoflavone, phenethyl isothiocyanate (PEITC), indole-3-carbinol, sulindac, and budesonide. Combinations of agents were also assayed. Since it is difficult to assess the efficacy of chemopreventives in clinical trials, it is essential to understand the mechanisms by which certain agents are expected to prevent smoke-related cancer. Preclinical studies are also useful to demonstrate the potential efficacy of chemopreventive agents. Unfortunately, until recently a suitable animal model for evaluating CS carcinogenicity and its chemoprevention was not available. We demonstrated that ECS and especially MCS become potently carcinogenic when exposure of mice starts at birth, as shown by very short latency times, high incidence and multiplicity of benign lung tumors, early occurrence of malignant lung tumors, and lesions in other organs. This mouse model was successfully used to demonstrate the ability of NAC, PEITC, and budesonide to prevent smoke-induced lung cancer, according to protocols mimicking the situation either in current smokers or in ex-smokers. Other dietary or pharmacological agents, including curcumin, anthocyanins, myo-inositol, SAHA, bexarotene and pioglitazone, are now under study. NAC was even successful to prevent lung cancer induced by MCS after birth when it was administered during the prenatal life. Therefore, it is now possible to investigate in vivo not only alterations of intermediate biomarkers but also the modulation of CS carcinogenesis by chemopreventive agents working with different mechanisms