Functional miRNA regulation of metastatic genes promotes tumor cell dissemination in non-small cell and small cell lung carcinomas

Abstract

Tumor progression, from initiation to advanced metastatic disease, requires the orchestration of a diverse group of cell-intrinsic and extrinsic factors. This multifactorial disease is promoted by an accumulation of genetic and epigenetic changes that confer selective advantage to cells and enable unrestrained proliferation, survival, motility, and self-renewal. While much emphasis over the last 35 years has been dedicated to understanding the regulators of tumor initiation, the number of cancer-related deaths worldwide continues to rise, of which the majority are attributed to metastasis. The lengthy progression to metastasis requires invasion out of the primary tumor site and into the bloodstream, survival in and exit from circulation, and colonization and expansion in a foreign environment. Developmental pathways such as the Transforming Growth Factor [beta] (TGF[beta]) signaling network are frequently dysregulated during metastatic progression due to the similarities between early embryogenesis and tumor progression. Furthermore, the TGF[beta] pathway highlights how cell-intrinsic and extrinsic signals help coordinate the complex interactions required between tumor cells, as well as those of the tumor microenvironment to achieve metastasis. Facilitating alterations to pathways such as TGF[beta] and many others are modulators of gene expression that can target multiple nodes of the signaling cascade instead of requiring genetic alterations to single genes. Moreover, in the last decade, emphasis on the role of noncoding RNAs in post-transcriptional modifications has revealed their important contribution in the regulation of developmental programs across metazoan species. More recently, the role of alterations in expression of small noncoding RNAs, microRNAs (miRNAs) has emerged as a significant contributor to disease states, including each stage of tumor progression from initiation to metastatic colonization. miRNAs hold great promise not only as biomarkers but also as potential therapeutics. For these reasons, we have characterized the role of two important examples of miRNA families - the miRNA-200 family and the miRNA-1 7~92 cluster - that regulate early stages of tumor initiation in addition to later steps of cell migration, invasion, survival, and colonization. Examination of their contribution to tumor progression in relevant in vitro and in vivo cellular contexts using genetic tools reveals they are functional contributors to tumor cell dissemination. Furthermore, modulation of their expression in the appropriate tumor microenvironments elucidates a network of targets underlying the molecular mechanisms of metastasis.