Cancer is one of the main causes of mortality worldwide. Geographical differences in incidence rates suggest a key effect of environmental factors, especially diet, in its aetiology. Epidemiologic and experimental studies have found a role of dietary lipids in cancer, particularly breast, colorectal, and prostate cancers. Their incidence in the Mediterranean countries, where the main source of fat is olive oil, is lower than in other areas of the world. Human studies about the effects of dietary lipids are little conclusive, probably due to methodological issues. On the other hand, experimental data have clearly demonstrated that the influence of dietary fats on cancer depends on the quantity and the type of lipids. Whereas a high intake of n-6 PUFA and saturated fat has tumor-enhancing effects, n-3 PUFA, conjugated linoleic acid and gamma-linolenic acid have inhibitory effects. Data regarding MUFA have not always been conclusive, but high olive oil diets seem to have protective effects. Such effects can be due to oleic acid, the main MUFA in olive oil, and to certain minor compounds such as squalene and phenolic compounds. This work aims to review the current knowledge about the relationship between dietary lipids and cancer, with a special emphasis on olive oil, and the molecular mechanisms underlying these effects: modifications on the carcinogenesis stages, hormonal status, cell membrane structure and function, signal transduction pathways, gene expression, and immune system.

BackgroundChanges in DNA methylation of crucial cancer genes including tumor suppressors can occur early in carcinogenesis, being potentially important early indicators of cancer. The objective of this study was to examine a multiplexed approach to assess the methylation of tumor suppressor genes as tumor stratification and clinical outcome prognostic biomarkers for lung cancer.MethodsA multicandidate probe panel interrogated DNA for aberrant methylation status in 18 tumor suppressor genes in lung cancer using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). Lung cancer cell lines (n = 7), and primary lung tumors (n = 54) were examined using MS-MLPA.ResultsGenes frequently methylated in lung cancer cell lines including SCGB3A1, ID4, CCND2 were found among the most commonly methylated in the lung tumors analyzed. HLTF, BNIP3, H2AFX, CACNA1G, TGIF, ID4 and CACNA1A were identified as novel tumor suppressor candidates methylated in lung tumors. The most frequently methylated genes in lung tumors were SCGB3A1 and DLC1 (both 50.0%). Methylation rates for ID4, DCL1, BNIP3, H2AFX, CACNA1G and TIMP3 were significantly different between squamous and adenocarcinomas. Methylation of RUNX3, SCGB3A1, SFRP4, and DLC1 was significantly associated with the extent of the disease when comparing localized versus metastatic tumors. Moreover, methylation of HTLF, SFRP5 and TIMP3 were significantly associated with overall survival.ConclusionsMS-MLPA can be used for classification of certain types of lung tumors and clinical outcome prediction. This latter is clinically relevant by offering an adjunct strategy for the clinical management of lung cancer patients.

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Objective: This trial aimed to evaluate the acceptability and efficacy of early timerestricted eating plus daily caloric restriction (E-TRE+DCR) compared with DCR alone within a behavioral weight-loss intervention. Methods: Participants (n = 81, 69 women, mean [SD] age: 38.0 [7.8] years, BMI: 34.1 [5.7] kg/m 2 ) were randomized to E-TRE (10-hour eating window starting within 3 hours of waking) plus DCR or DCR alone (~35% DCR) for 39 weeks. The primary outcome was body weight (measured with digital scale) at week 12. Secondary outcomes measured at week 12 included hemoglobin A1c, lipids, energy intake (photographic food records), physical activity (accelerometry), dietary adherence (questionnaires), and body composition (dual-energy x-ray absorptiometry). Weight and body composition were also assessed at week 39. Results: Mean [SD] weight loss was not different between groups at week 12

KiSS-1 is a metastasis suppressor gene reported to be involved in the progression of several solid neoplasias. The loss of KiSS-1 gene expression has been shown to be inversely correlated with increasing tumor stage, distant metastases, and poor overall survival in bladder tumors. To identify the molecular pathways associated with the metastasis suppressor role of KiSS-1 in bladder cancer, we carried out a proteomics analysis of bladder cancer cells (EJ138) transiently transfected with a vector encompassing the full-length KiSS-1 gene using an iTRAQ (isobaric tags for relative and absolute quantitation) approach. Protein extracts collected after 24-and 48-h transfection were fractionated and cleaved with trypsin, and the resulting peptides were labeled with iTRAQ reagents. The Bladder cancer represents the fourth most common malignancy among men and the eighth cause of male cancer deaths (1). Bladder cancer can be classified based on the depth of invasion. Clinically, ϳ75% of transitional cell carcinomas (TCCs) 1 are non-muscle-invasive (pTis, pTa, and pT1), 20% are muscle infiltrating (pT2-pT4), and 5% are metastatic at the time of diagnosis (1). Low grade tumors are always papillary and usually non-invasive, whereas high grade tumors can be either papillary or non-papillary and are often invasive. Patients diagnosed with localized TCC have a 5-year relative survival rate over 90%. However, patients presenting with regional and distant metastatic disease spread have 5-year relative survival rates of lower than 50 and 10%, respectively (1). Bladder cancer progression and the development of secondary metastases follow complex sequential steps. The changes at the genetic and/or epigenetic level to the many genes involved in critical cell functions are not completely understood (2).KiSS-1 has been shown to suppress metastases without affecting tumorigenicity in melanoma and breast cancer cells (3-7). It maps to chromosome 1q32 (8) and is regulated by genes mapping to chromosome 6 (3-7). KiSS-1 encodes a 145-amino acid protein, which is processed into kisspeptins of several sizes (9 -11). Kisspeptins have been shown to control the onset of puberty and inhibit cancer metastasis of different tumor types (9 -11). Experimental and clinical studies indicate KiSS-1 to be a functionally active metastasis suppressor gene in several solid tumors (12-19). Molecular profiling analysis revealed that KiSS-1 was lost in advanced cell 1 The abbreviations used are: TCC, transitional cell carcinoma; EF, error factor; FDR, false discovery rate; iTRAQ, isobaric tags for relative and absolute quantitation; RB, retinoblastoma; TP53, tumor protein 53; CI, confidence interval; EV, empty vector; Ct, cycle threshold. Research

KISS1 is a metastasis suppressor gene that is lost in several malignancies, including bladder cancer. We tested the epigenetic silencing hypothesis and evaluated the biological influence of KISS1 methylation on its expression and clinical relevance in bladder cancer. KISS1 hypermethylation was frequent in bladder cancer cells analyzed by methylation-specific PCR and bisulfite sequencing and was associated with low gene expression, being restored in vitro by demethylating azacytidine. Hypermethylation was also frequently observed in a large series of bladder tumors (83.1%, n ‫؍‬ 804). KISS1 methylation was associated with increasing stage (P ‫؍‬ 0.001) and tumor grade (P ‫؍‬ 0.010). KISS1 methylation was associated with low KISS1 transcript expression by quantitative RT-PCR (P ‫؍‬ 0.037). KISS1 transcript expression was also associated with histopathological tumor stage (P < 0.0005). Low transcript expression alone (P ‫؍‬ 0.003) or combined with methylation (P ‫؍‬ 0.019) was associated with poor disease-specific survival (n ‫؍‬ 205).KISS1 transcript expression remained an independent prognosticator in multivariate analyses (P ‫؍‬ 0.017). KISS1 hypermethylation was identified in bladder cancer, providing a potential mechanistic explanation (epigenetic silencing) for the observed loss of KISS1 in uroepithelial malignancies. Associations of KISS1 methylation and its expression with histopathological variables and poor survival suggest the utility of incorporating KISS1 measurement using paraffin-embedded material for tumor stratification and clinical outcome prognosis of patients with uroepithelial neoplasias.

Changes in DNA methylation of tumor suppressors can occur early in carcinogenesis and are potentially important early indicators of cancer. The objective of this study was to assess the methylation of 25 tumor suppressor genes in bladder cancer using a methylation-specific (MS) multiplex ligation-dependent probe amplification assay (MLPA). Initial analyses in bladder cancer cell lines (n ‫؍‬ 14) and fresh-frozen primary bladder tumor specimens (n ‫؍‬ 31) supported the panel of genes selected being altered in bladder cancer. The process of MS-MLPA was optimized for its application in body fluids using two independent training and validation sets of urinary specimens (n ‫؍‬ 146), including patients with bladder cancer (n ‫؍‬ 96) and controls (n ‫؍‬ 50). BRCA1 (71.0%), WT1 (38.7%), and RARB (38.7%) were the most frequently methylated genes in bladder tumors, with WT1 methylation being significantly associated with tumor stage (P ‫؍‬ 0.011). WT1 and PAX5A were identified as methylated tumor suppressors. In addition, BRCA1, WT1, and RARB were the most frequently methylated genes in urinary specimens. Receiver operating characteristic curve analyses revealed significant diagnostic accuracies in both urinary sets for BRCA1, RARB, and WT1.

Extra-virgin olive oil (EVOO) has been hypothesized to have chemopreventive effects on breast cancer, unlike high corn oil (HCO) diets that stimulate it. We have investigated mechanisms of these differential modulatory actions on experimental mammary cancer. In 7,12-dimethylbenz(a)anthracene adenocarcinomas of rats fed a high EVOO, HCO and control diets (n = 20 for each group), we have analyzed the expression and activity of ErbB receptors, p21Ras and its extracellular signal-regulated kinase (ERK) 1/2, Akt and RalA/B effectors by immunoblotting analyses. We explored the Ha-ras1 mutation status by Southern blot, mismatch amplification mutation assay and sequencing, and the 3-hydroxy-3-methylglutaryl-coenzyme A reductase and squalene synthase messenger RNA expression by real-time polymerase chain reaction. We analyzed the tumor mitotic index, proliferating cell nuclear antigen (PCNA) levels, and apoptosis through Caspase-3 analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assays. Finally, we measured the 8-oxo-2'-deoxyguanosine levels. Non-parametrical statistics were used. The EVOO diet decreased Ras activation, downregulated the Ras/phosphatidyl inositol 3-kinase/Akt pathway and upregulated the Raf/Erk pathway, compared with the control. In contrast, the HCO diet did not modify Ras activity but rather enhanced the Raf/Erk pathway. The EVOO diet decreased the cleaved ErbB4 levels, compared with the HCO diet, increased apoptosis and diminished the mono-ubiquitylated PCNA levels, which is related to DNA damage. Tumors from rats fed the EVOO diet displayed a more benign phenotype, whereas those from rats fed the HCO diet were biologically more aggressive. In conclusion, high EVOO and corn oil diets exert their modulatory effects on breast cancer through a different combination of Ras signaling pathways, a different proliferation-apoptosis balance and probably distinct levels of DNA damage.