Mir 145/143: tumor suppressor, oncogenic microenvironmental factor or …both?

literature regarding the role of mir-143/145 in tumor initiation/progression. Herein, we aim to contribute our experience and observations to this ongoing debate. We will start from the experimental data presented in the outstanding work of the Tyler Jacks lab, by Dimitrova, Gocheva and colleagues [6]. They show, in a kRAS/p53 murine model of lung adenocarcinoma, that the contribution of the microRNA 143/145 cluster to lung cancer development is non-cell autonomous with the expression of mir143/145 from the tumor micro-environment resulting protumorigenic. More specifically, higher expression of microRNA 143/145 by endothelial cells would be pivotal in tumor progression by favoring tumor angiogenesis in a lung tissue specific fashion. The authors conclude, and their conclusion is shared by Almeida and Calin in a commentary on Genome Biology [1], that mir-143/145 is a non-cell autonomous oncogenic factor rather than a tumor suppressor, with their speculation further supported by the absence of tumor development in mice devoid of such microRNAs and by their lack of expression in murine epithelial cell lines [6]. This is in apparent contrast to what was published by our group and by many others, who provided evidence for the roles that mir-143/145 play as tumor suppressors in human tumors of epithelial origin, including and not limited to cervical, colon, gastric, breast and pancreatic carcinomas, NSCLC and malignant pleural mesothe-lioma (reviewed in Das and Pillai, 2015) [5]. In their commentary, Almeida and Calin claim that the " heterogeneity " of the human tumors collected for the human studies has prevented to provide a precise definition of the mir143/145 role. They basically substantiate such observation with the possibility that, in unfractionated human tumor tissues, residual expression of mir-143/145 by stromal component may escape the analysis of unfractionated human tumors. Even though this is certainly possible, we will try to provide a "parallel" and not mutually exclusive vision to integrate the ongoing discussion, starting from the work by Dimitrova et al. [6]. First, the data supporting a non-cell autonomous oncogenic role for the mir143/145 derive from a murine Letters to the Editors system. Dimitrova and coworkers employed an excellent albeit limited experimental system. In fact, while mice were engineered to express/not express specific tumor suppressors or oncogenes, represent an invaluable tool to study tumor progression, however there is little doubt left that such a system may reflect, at its best, one or few subtypes of its human counterparts of which it may recapitulate …