Genomic Analysis of Long Non-Coding RNAs in TGF-β Signaling and Cancer Metastasis

Abstract

Cancer, the second leading cause of death in the United States, represents a major public health problem worldwide. Since metastases account for the vast majority of cancer-related deaths, understanding the process of metastasis is vital to improving diagnosis and treatment of the disease. One of the signaling pathways that has been implicated in tumor progression is the transforming growth factor β (TGF-β) pathway. TGF-β has a dual role in cancer pathogenesis: it can act as a tumor suppressor through its potent anti-proliferative effects, but it can also act as a tumor promoter through various mechanisms, including enhancing invasiveness of tumor cells. The recently discovered class of RNAs known as the long non-coding RNAs (lncRNAs) has been shown to have a variety of functional roles, including effects on the progression of cancer. In this study, we examine the role of lncRNAs in tumor metastasis, specifically in the TGF-β signaling pathway. Using microarray gene expression data from three epithelial cell lines, we identified lncRNAs common to the short-term TGF-β response across multiple cell types. After validating the differential expression of these candidates, we generated cell lines overexpressing the lncRNAs of interest. Although overexpression of the lncRNAs tested thus far did not affect cell growth or cell cycle control, we have shown that their expression level is significantly higher in cancer cell lines compared to normal cells, indicating an association between these lncRNAs and cancer. Furthermore, we found that the differentially expressed lncRNAs had a higher number of microRNA (miRNA) binding sites, suggesting miRNA regulation as a possible mechanism of action. Although we have not conclusively established the specific pathways and processes affected by candidate lncRNAs, studies are ongoing to better understand their functions in TGF-β signaling and tumorigenesis. Our results highlight the validity of the approach used in identifying lncRNAs that are not only biologically but also clinically meaningful and provide the foundation for future studies to elucidate the role of lncRNAs in TGF-β signaling and cancer metastasis.