A step-by-step microRNA guide to cancer development and metastasis

Georgios S. Markopoulos, Eugenia Roupakia, Maria Tokamani, Evangelia Chavdoula, Maria Hatziapostolou, Christos Polytarchou, Kenneth B. Marcu, Athanasios G. Papavassiliou, Raphael Sandaltzopoulos, Evangelos Kolettas

Cancer is one of the leading causes of mortality. The neoplastic transformation of normal cells to cancer cells is caused by a progressive accumulation of genetic and epigenetic alterations in oncogenes, tumor suppressor genes and epigenetic regulators, providing cells with new properties, collectively known as the hallmarks of cancer. During the process of neoplastic transformation cells progressively acquire novel characteristics such as unlimited growth potential, increased motility and the ability to migrate and invade adjacent tissues, the ability to spread from the tumor of origin to distant sites, and increased resistance to various types of stresses, mostly attributed to the activation of genetic stress-response programs. Accumulating evidence indicates a crucial role of microRNAs (miRNAs or miRs) in the initiation and progression of cancer, acting either as oncogenes (oncomirs) or as tumor suppressors via several molecular mechanisms. MiRNAs comprise a class of small ~22 bp long noncoding RNAs that play a key role in the regulation of gene expression at the post-transcriptional level, acting as negative regulators of mRNA translation and/or stability. MiRNAs are involved in the regulation of a variety of biological processes including cell cycle progression, DNA damage responses and apoptosis, epithelial-to-mesenchymal cell transitions, cell motility and stemness through complex and interactive transcription factor-miRNA regulatory networks. The impact and the dynamic potential of miRNAs with oncogenic or tumor suppressor properties in each stage of the multistep process of tumorigenesis, and in the adaptation of cancer cells to stress, are discussed. We propose that the balance between oncogenic versus tumor suppressive miRNAs acting within transcription factor-miRNA regulatory networks, influences both the multistage process of neoplastic transformation, whereby normal cells become cancerous, and their stress responses. The role of specific tumor-derived exosomes containing miRNAs and their use as biomarkers in diagnosis and prognosis, and as therapeutic targets, are also discussed.