The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs

Abstract

BackgroundThe TGFβ-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression.MethodsIn this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFβ-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months.ResultsThirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months.ConclusionThese data support an interaction between miRNAs and genes in the TGFβ-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1566-8) contains supplementary material, which is available to authorized users.

Serum miRNAs associated with tumor-promoting cytokines in non-small cell lung cancer

“…There are accumulating studies showing that miRNAs associate with tumorigenesis through the regulation of cytokine production [ 11 – 13 ]. We found a moderate correlation between TGF-β concentration and expression levels of miR-20a and miR-223, and a weak correlation between VEGF concentration and expression levels of miR-20a and miR-223.…”

“…Several studies have revealed that the expression levels display oscillatory changes in response to TNF-α in macrophage cells [ 9 ], and VEGF and IL-6 in bone marrow mesenchymal stromal cells [ 10 ]. Moreover, changes in miRNA expression have been demonstrated to be involved with cytokine signaling pathways in several types of cancers, including colorectal [ 11 ], breast [ 12 ], and lung [ 13 ] cancers. Although there has been accumulating evidence to support the regulation of cytokines by miRNAs, studies conducted to determine the association of miRNAs and tumor-promoting cytokines in clinical samples in lung cancer are limited.…”

A Multi-Omics Analysis of Bone Morphogenetic Protein 5 (BMP5) mRNA Expression and Clinical Prognostic Outcomes in Different Cancers Using Bioinformatics Approaches

“…Mutation in BMP5 is associated with a wide range of skeletal defects such as reduction in the long bone width and the size of the vertebral processes as well as the reduction of lower body mass [7,8]. It has been reported that BMP, together with its subtype BMP5, is involved in the initiation of several types of cancers such as colon, lung, breast, bladder, and ovarian cancer [9][10][11][12][13][14][15][16]. Previous studies on colorectal cancer showed a significant correlation between BMP5 down-expression and mutation and the prognostic value of colorectal cancer (CRC), triggering the initiation and development of tumors [12,14,15].…”

“…It has been reported that BMP, together with its subtype BMP5, is involved in the initiation of several types of cancers such as colon, lung, breast, bladder, and ovarian cancer [9][10][11][12][13][14][15][16]. Previous studies on colorectal cancer showed a significant correlation between BMP5 down-expression and mutation and the prognostic value of colorectal cancer (CRC), triggering the initiation and development of tumors [12,14,15]. One study reported that 13 cases of BMP5 mutation across seven cancers where gastrointestinal cancers (GICs) were the most influenced by recurrent hotspot mutations [13].…”

The Relationship Between the PPARδ-87T&gt;C Polymorphism and Colorectal Cancer Risk in a Chinese Han Population

“…CRC exhibits a complex and multifactorial pathogenesis that is incompletely understood. The development of colorectal tumors is thought to arise through the accumulation of genetic mutations [8], microsatellite instability [9], telomerase activation [10], epigenetic alterations [11], and signaling dysregulation [12][13][14]. There is also increasingly robust evidence that the gut microbiome can regulate key signaling pathways and immunological responses associated with the growth or suppression of CRC tumors [15].…”