Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial–mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149–59. ©2016 AACR

Epigenomics of breast cancer

Breast cancer is the second most common malignant cancer and accounts for 1.38 million of the total new cancer cases and 458,400 of the total cancer deaths reported in 2008. Breast cancer with several subtypes is an extremely heterogeneous disease caused by interaction of both genetic and environmental risk factors. In order to understand the etiology of this heterogeneity, new perspectives like epigenetics are needed. The term epigenetics was coined by Conrad Hal Waddington in the early 1940s. It refers to the study of gene function and regulation alterations without changes in the DNA sequence of the genome. The main epigenetic modifications are DNA methylation, histone modifications, and small noncoding RNAs (miRNAs). DNA methylation is the first to be associated with cancer and the most widely studied among epigenetic modifications. It regulates the gene expression by modifying the accessibility of DNA to the transcriptional machinery. The importance of histone modification has been realized during the last 10 years, after identification of the coexistence of histone modifications. From the dynamically changing pattern of histone modification has emerged a new concept termed histone cross talk. The epigenetic modifications are faster and reversible than mutation and easily affected by aging, environmental stimuli, and food in heritable manner. These characteristics provide a vital position in the etiology of diseases. After several investigations, it is well understood that the epigenetic modifications are involved in not only many biological processes such as X-chromosome inactivation, genomic imprinting, RNA interference, and programming of the genome but also several disease like breast cancer. Today we realize that the accumulation of epigenetic modifications occurs in the development of breast cancer. In addition, the epigenetic modifications improve our knowledge about the biology and heterogeneity of breast cancer by large-scale methods. Therefore, the researchers focused on epigenetic alterations-based breast cancer therapy, and it is speculated that epigenetic modifications may be markers for breast cancer. It is likely that epigenetics-based therapy will become a reality in the near future. © 2014 Springer India. All rights reserved