Abstract
Long non-coding RNAs (lncRNAs) are the most heterogeneous class of non-protein-coding RNAs involved in a broad spectrum of molecular mechanisms controlling genome function, including the generation of complex networks of RNA-RNA competitive interactions. Accordingly, their dysregulation contributes to the onset of many tumors, including colorectal cancer (CRC). Through a combination of in silico approaches (statistical screening of expression datasets) and in vitro analyses (enforced expression, artificial inhibition, or activation of pathways), we identified LINC00483 as a potential tumor suppressor lncRNA in CRC. LINC00483 was downregulated in CRC biopsies and metastases and its decreased levels were associated with severe clinical features. Inhibition of the MAPK pathway and cell cycle arrest by starvation induced an upregulation of LINC00483, while the epithelial to mesenchymal transition activation by TGFβ-1 and IL-6 caused its down-modulation. Moreover, enforced expression of LINC00483 provoked a slowing down of cell migration rate without affecting cell proliferation. Since LINC00483 was predominantly cytoplasmic, we hypothesized a “miRNA sponge” role for it. Accordingly, we computationally reconstructed the LINC00483/miRNA/mRNA axes and evaluated the expression of mRNAs in different experimental conditions inducing LINC00483 alteration. By this approach, we identified a set of mRNAs sharing the miRNA response elements with LINC00483 and modulated in accordance with it. Moreover, we found that LINC00483 is potentially under negative control of transcription factor HNF4α. In conclusion, we propose that LINC00483 is a tumor suppressor in CRC that, through an RNA-RNA network, may control cell migration and participate in proliferation signaling.
Highlights
Colorectal cancer (CRC) is the most common malignancy in the digestive system and the fourth leading cause of cancer-related death around the world, mainly from tumor metastasis [1]
By following the approach reported in methods, we identified from each CRC expression dataset those genes that were downregulated/upregulated in CRC, according to the specified clinical-pathological features
By screening several CRC datasets, we found that LINC00483 expression correlated with several protein-coding genes whose dysregulation was associated with CRC
Summary
Colorectal cancer (CRC) is the most common malignancy in the digestive system and the fourth leading cause of cancer-related death around the world, mainly from tumor metastasis [1]. The Vogelstein’s model, based on a sequence of molecular changes within protein-coding genes leading to cancer transformation, is considered too simplistic to explain the complex heterogeneity of cancer, including and especially CRC [2, 3]. According to the hypothesis that the expressions of lncRNAs and mRNAs with the same MREs would be positively and negatively correlated to each other and to miRNAs, respectively, in this paper we propose a combined approach of in silico and experimental biology to identify an lncRNA whose dysregulated expression is associated with CRC pathobiology. Based on the hypothesis that RNA-RNA network functioning is grounded on relative stoichiometric concentrations of interacting RNA molecules, our aim was the identification and characterization of a lncRNA whose expression was linearly related to that of mRNAs dysregulated in association with most serious clinical features of CRC patients. LINC00483 was experimentally analysed to understand its involvement in CRC and its associated molecular axes
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