Role of miRNAs in Cancer

MicroRNAs are the best representatives of the non-coding part of the genome and their functions are mostly linked to their target genes. During the process of carcinogenesis, both dysregulation of microRNAs and their target genes can explain the development of the disease. However, most of the target genes of microRNAs have not yet been elucidated. In this book, we add new information related to the functions of microRNAs in various tumors and their associated targetome

Strategies on the use of Nucleolar Function Inhibitors in cancer therapy

Kidney cancer is the 7th most common cancer in the UK with over 13,300 new cases and about 4,709 deaths per annum (1). Renal cell carcinoma (RCC) accounts for 85% of kidney cancers and stage at diagnosis for this type of kidney cancer is strongly associated with patient outcome with barely 12% 5-year survival rate in patients diagnosed with advanced RCC (2). Patients with metastatic RCC are often treated with systemic treatment, including chemotherapy, targeted therapy and immunotherapy, however, narrowed therapeutic indices limit their use as the high toxicity severely affects the patients’ quality of life and ability to follow through treatment regimens (3–5). The present thesis proposes a strategy to sensitise RCC cells to the effects of nucleolar function inhibitors (NFIs), particularly considering that changes in the morphology of the nucleoli are associated with high aggressiveness and poor prognosis of RCC patients (6), and the role that dysregulated nucleolar activity plays on increased proliferation of cancer cells (7). Given the fact that nucleolar function is modulated by cellular pathways for which targeted therapies have already been developed and are currently used to treat RCC, such as the mechanistic target of rapamycin (mTOR) pathway (8,9), the aims of this research are to determine whether mTOR inhibitors effectively modulate nucleolar function of RCC in vitro, to identify potential candidates for target-sensitised chemotherapy, and finally, to assess the effect of the drug combinations proposed. Microplate-based ribosomal RNA (rRNA) synthesis analysis using click chemistry revealed that ATP-competitive inhibitor Torin 1, but not the allosteric mTOR inhibitors Rapamycin, Temsirolimus and Everolimus, inhibits nucleolar function in ACHN and UoK111 cells. This was consistent with inhibition of cell viability and induction of cell cycle arrest achieved only by Torin 1 in the same cell lines, shown with MTT assay and flow cytometry, respectively. While treatment with both allosteric and ATP-competitive inhibitors of mTOR effectively reduced mTOR activity, as exemplified by the inhibition of the phosphorylation of mTOR complex 1 (mTORC1) substrate S6K and the changes in the phosphorylation patterns of 4EBP1 observed using Western Blot, only Torin 1 inhibited the phosphorylation of the RNA Polymerase I (RNA Pol I) transcription factor TIF-IA, which is a downstream target of mTOR, suggesting that decrease cell viability of RCC cells in the presence of Torin 1 might be mediated by the ability of this compound to modulate the nucleolar function. Subsequent study of the effects of the combination of Actinomycin D (ActD) and ATP-competitive mTOR inhibitors on cell viability and rRNA synthesis performed with MTT assay and microplate-based rRNA synthesis analysis using click chemistry and isobolographic analysis of the drug interactions, suggest that ATP-competitive mTOR inhibitors can sensitise RCC cells to the cytotoxic effects of ActD. Ultimately, the findings described in this thesis present the opportunity for a novel strategy for the treatment of RCC, targeting the nucleolus, which plays an important role in RCC, while taking advantage of the existing therapeutic agents. Specifically, we propose that combination of ATP-competitive mTOR inhibitors with the NFI ActD sensitises RCC cells to the cytotoxic effects of ActD, a strategy we termed target-sensitised chemotherapy

PPARs as Key Mediators of Metabolic and Inflammatory Regulation

Mounting evidence suggests a bidirectional relationship between metabolism and inflammation. Molecular crosstalk between these processes occurs at different levels with the participation of nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). There are three PPAR isotypes, α, β/δ, and γ, which modulate metabolic and inflammatory pathways, making them key for the control of cellular, organ, and systemic processes. PPAR activity is governed by fatty acids and fatty acid derivatives, and by drugs used in clinics (glitazones and fibrates). The study of PPAR action, also modulated by post-translational modifications, has enabled extraordinary advances in the understanding of the multifaceted roles of these receptors in metabolism, energy homeostasis, and inflammation both in health and disease. This Special Issue of IJMS includes a broad range of basic and translational article, both original research and reviews, focused on the latest developments in the regulation of metabolic and/or inflammatory processes by PPARs in all organs and the microbiomes of different vertebrate species

RNA, the Epicenter of Genetic Information

The origin story and emergence of molecular biology is muddled. The early triumphs in bacterial genetics and the complexity of animal and plant genomes complicate an intricate history. This book documents the many advances, as well as the prejudices and founder fallacies. It highlights the premature relegation of RNA to simply an intermediate between gene and protein, the underestimation of the amount of information required to program the development of multicellular organisms, and the dawning realization that RNA is the cornerstone of cell biology, development, brain function and probably evolution itself. Key personalities, their hubris as well as prescient predictions are richly illustrated with quotes, archival material, photographs, diagrams and references to bring the people, ideas and discoveries to life, from the conceptual cradles of molecular biology to the current revolution in the understanding of genetic information. Key Features Documents the confused early history of DNA, RNA and proteins - a transformative history of molecular biology like no other. Integrates the influences of biochemistry and genetics on the landscape of molecular biology. Chronicles the important discoveries, preconceptions and misconceptions that retarded or misdirected progress. Highlights major pioneers and contributors to molecular biology, with a focus on RNA and noncoding DNA. Summarizes the mounting evidence for the central roles of non-protein-coding RNA in cell and developmental biology. Provides a thought-provoking retrospective and forward-looking perspective for advanced students and professional researchers

Saliva and Oral Diseases

This book represents a guide to the academic, scientific and clinical applications of saliva as a diagnostic fluid. This volume is written by leaders in multiple fields and fulfills a demand for a broad understanding of saliva across a range of disciplines