Therapeutic value of restoration of tumor suppressor microRNAs in the development of lung cancer

MicroRNAs (miRNAs) are molecules that regulate gene expression and as such they collaborate to determine how many proteins are produced in the cells of a given gene. As their name indicates, they are functional molecules despite their small size (micro) and are made up of ribonucleic acid (RNA), in contrast to the most extensively studied regulators of gene expression, which are protein in nature. Due to its small size and peculiar nature, the presence of the genes that encode microRNAs was discovered in the human genome in stages after its sequencing, already in the 21st century. MicroRNAs play a fundamental role in establishing cellular identity and function. Therefore, components of the microRNA synthesis machinery, or microRNAs per se, have been associated with various human pathologies, including cancer. It has been discovered that microRNAs play an important role in many cellular processes that are altered in cancer such as: differentiation, proliferation, and apoptosis. The genes that code for microRNAs have been found in chromosomal regions frequently gained or lost in cancer. Some microRNAs have altered expression levels in cancer and have demonstrated their ability to affect cellular transformation, carcinogenesis, and metastasis by acting as oncogenes or tumor suppressor genes. Thus, the presence of certain microRNAs has been seen to have clinical diagnostic and prognostic utility and attempts are being made to validate therapies based on the activity of relevant microRNAs in cancer. The let-7 family of microRNAs was the first discovered in humans. Many of its members are in chromosomal regions frequently deleted in lung cancer tumors. Furthermore, reduced expression of these genes has been correlated with a worse lung cancer prognosis. It is thought that the role of let-7 as a tumor suppressor is due to the fact that it is capable of inhibiting the synthesis of important oncogenes such as RAS, MYC and HMGA2 and that of proteins involved in cell cycle progression such as CDC25A, CDK6 and Cyclin D2. In the present work, experimental results are collected that indicate that the loss of function of let-7 favors tumor development in a mouse tumor model, suggesting the hypothesis that the activity of let-7 collaborates to prevent tumor formation. On the other hand, results are presented that indicate that the reintroduction of let-7 activity in already established lung tumors significantly hinders their growth, even entering regression. These preclinical results demonstrate the antitumor therapeutic potential of let-7 activity and that its reintroduction into lung tumors could have clinical utility if it could be performed efficiently and safely.