An Immunocompetent Environment Unravels the Proto-Oncogenic Role of miR-22

Through their regulatory activity of gene expression, microRNAs have been heavily implicated in the genesis of cancer. They can act both as promoters (oncogenes) and suppressors of tumorigenesis. They can work within cells but also be secreted and uptaken by cells. While in certain instances, microRNAs appear to unequivocally act as oncogenes or tumor suppressor genes, in other instances, their activity appears to be tissue or context-dependent, in seemingly contradictory reports. MiR-22 has been extensively studied because of its powerful and diverse biological activities and has been attributed to both oncogenic and tumor-suppressive abilities. In this article, we critically analyzed this vast literature and reassessed the status of the miR-22 genetic locus in human cancer. We conclude that, when studied in immunocompetent model systems, miR-22 invariably acts as a tumor-promoting miRNA in view of its ability to impact the cancer immune microenvironment. MiR-22 was first identified as a proto-oncogenic microRNA (miRNA) due to its ability to post-transcriptionally suppress the expression of the potent PTEN (Phosphatase And Tensin Homolog) tumor suppressor gene. miR-22 tumorigenic role in cancer was subsequently supported by its ability to positively trigger lipogenesis, anabolic metabolism, and epithelial-mesenchymal transition (EMT) towards the metastatic spread. However, during the following years, the picture was complicated by the identification of targets that support a tumor-suppressive role in certain tissues or cell types. Indeed, many papers have been published where in vitro cellular assays and in vivo immunodeficient or immunosuppressed xenograft models are used. However, here we show that all the studies performed in vivo, in immunocompetent transgenic and knock-out animal models, unanimously support a proto-oncogenic role for miR-22. Since miR-22 is actively secreted from and readily exchanged between normal and tumoral cells, a functional immune dimension at play could well represent the divider that allows reconciling these contradictory findings. In addition to a critical review of this vast literature, here we provide further proof of the oncogenic role of miR-22 through the analysis of its genomic locus vis a vis the genetic landscape of human cancer.