Topic
Carcinogenesis
About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.
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TL;DR: It is shown that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells and demonstrates a pivotal role for Sirt7 in chromatin regulation, cellular transformation programs and tumour formation in vivo.
Abstract: Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD(+)-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo.
495 citations
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TL;DR: The observations thatSkp2 can mediate transformation and is up-regulated during oral epithelial carcinogenesis support a role for Skp2 as a protooncogene in human tumors.
Abstract: Skp2 is a member of the F-box family of substrate-recognition subunits of SCF ubiquitin–protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G1 progression, including the cyclin-dependent kinase inhibitor p27, a dosage-dependent tumor suppressor protein. In this study, we examined Skp2 and p27 protein expression by immunohistochemistry in normal oral epithelium and in different stages of malignant oral cancer progression, including dysplasia and oral squamous cell carcinoma. We found that increased levels of Skp2 protein are associated with reduced p27 in a subset of oral epithelial dysplasias and carcinomas compared with normal epithelial controls. Tumors with high Skp2 (>20% positive cells) expression invariably showed reduced or absent p27 and tumors with high p27 (>20% positive cells) expression rarely showed Skp2 positivity. Increased Skp2 protein levels were not always correlated with increased cell proliferation (assayed by Ki-67 staining), suggesting that alterations of Skp2 may contribute to the malignant phenotype without affecting proliferation. Skp2 protein overexpression may lead to accelerated p27 proteolysis and contribute to malignant progression from dysplasia to oral epithelial carcinoma. Moreover, we also demonstrate that Skp2 has oncogenic potential by showing that Skp2 cooperates with H-RasG12V to malignantly transform primary rodent fibroblasts as scored by colony formation in soft agar and tumor formation in nude mice. The observations that Skp2 can mediate transformation and is up-regulated during oral epithelial carcinogenesis support a role for Skp2 as a protooncogene in human tumors.
494 citations
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TL;DR: Current evidence from experimental and human studies is summarized that implicates a high intake of omega-6 PUFAs in cancer of the breast, colon and, possibly, prostate and which indicates that omega-3PUFAs and monounsaturated fatty acids such as oleic acid (omega-9) are protective.
Abstract: The hypothesis that a high-fat diet promotes the development of postmenopausal breast cancer is supported by international data showing a strong correlation between fat intake and breast cancer rates and a modest positive association with high-fat diet in case-control studies. Dietary fat intake was found to be unrelated to the risk of breast cancer in cohort studies. In view of these conflicting findings it has been difficult to make nutritional recommendations for the prevention of breast cancer. Studies in animal models and recent observations in humans, however, have provided evidence that a high intake of omega-polyunsaturated fatty acids (PUFAs), stimulates several stages in the development of mammary and colon cancer, from an increase in oxidative DNA damage to effects on cell proliferation, free estrogen levels to hormonal catabolism. In contrast, fish oil-derived omega-3 fatty acids seem to prevent cancer by influencing the activity of enzymes and proteins related to intracellular signalling and, ultimately, cell proliferation. In this commentary, current evidence from experimental and human studies is summarized that implicates a high intake of omega-6 PUFAs in cancer of the breast, colon and, possibly, prostate and which indicates that omega-3 PUFAs and monounsaturated fatty acids such as oleic acid (omega-9) are protective. Plausible mechanisms for modulation of steps in the multistage carcinogenesis process by fats are discussed. Properly designed epidemiological studies are now needed, that integrate relevant biomarkers to unravel the contributions of different types of fat, their interactions with hormonal catabolism, protective nutritional factors and human cancer risk.
494 citations
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TL;DR: In vivo and in vitro results show that the genomic instability persists after transformation and that microsatellite mutations accumulate as consecutive somatic slippage events of a single or a few repeated units.
Abstract: Genomic instability at simple repeated sequences (SRS) is a landmark for some sporadic and hereditary cancers of the colon. We have identified several human tumour cell lines with up to 1,000–fold increases in mutation rates for endogenous microsatellite sequences, relative to normal cells or tumour cells without the mutator phenotype and show that they are very early events in tumorigenesis. Our in vivo and in vitro results show that the genomic instability persists after transformation and that microsatellite mutations accumulate as consecutive somatic slippage events of a single or a few repeated units. This mechanism may account for the repeat expansions in triplet hereditary diseases and the same defect in replication fidelity in non–polyposis colon cancer could also contribute to the non–mendelian anticipation in these diseases.
494 citations
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TL;DR: Findings indicate that LNA-1 acts as a transcription co-factor and may contribute to KSHV-induced oncogenesis by targeting the retinoblastoma protein–E2F transcriptional regulatory pathway.
Abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is involved in the etiopathogenesis of Kaposi sar-coma and certain lymphoproliferative disorders. Open reading frame (ORF) 73 encodes the main immunogenic latent nuclear antigen (LNA-1) of KSHV. LNA-1 maintains the KSHV episome and tethers the viral genome to chromatin during mitosis. In addition, LNA-1 interacts with p53 and represses its transcriptional activity. Here we show that LNA-1 also interacts with the retinoblastoma protein. LNA-1 transactivated an artificial promoter carrying the cell cycle transcription factor E2F DNA-binding sequences and also upregulated the cyclin E (CCNEI) promoter, but not the B-myb (MYBL2) promoter. LNA-1 overcame the flat-cell phenotype induced by retinoblastoma protein in Saos2 cells. In cooperation with the cellular oncogene Harvey rat sarcoma viral oncogene homolog (Hras), LNA-1 transformed primary rat embryo fibroblasts and rendered them tumorigenic. These findings indicate that LNA-1 acts as a transcription co-factor and may contribute to KSHV-induced oncogenesis by targeting the retinoblastoma protein-E2F transcriptional regulatory pathway.
493 citations