Long non-coding RNAs and TGF-β signaling in cancer

Cancer is driven by genetic mutations in oncogenes and tumor suppressor genes and by cellular events that develop a misregulated molecular microenvironment in the growing tumor tissue. The tumor microenvironment is guided by the excessive action of specific cytokines including transforming growth factor-beta (TGF-beta), which normally controls embryonic development and the homeostasis of young or adult tissues. As a consequence of the genetic alterations generating a given tumor, TGF-beta can preserve its homeostatic function and attempt to limit neoplastic expansion, whereas, once the tumor has progressed to an aggressive stage, TGF-beta can synergize with various oncogenic stimuli to facilitate tumor invasiveness and metastasis. TGF-beta signaling mechanisms via Smad proteins, various ubiquitin ligases, and protein kinases are relatively well understood. Such mechanisms regulate the expression of genes encoding proteins or non-coding RNAs. Among non-coding RNAs, much has been understood regarding the regulation and function of microRNAs, whereas the role of long non-coding RNAs is still emerging. This article emphasizes TGF-beta signaling mechanisms leading to the regulation of non-coding genes, the function of such non-coding RNAs as regulators of TGF-beta signaling, and the contribution of these mechanisms in specific hallmarks of cancer.