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Published on: July 22, 2020
The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs
Andrew J Pellatt1, Lila E Mullany2, Jennifer S Herrick2
1School of Medicine, Tulane University, New Orleans, LA, USA.
Background:
The 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.
Methods:
In 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.
Results:
Thirteen 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.
Conclusion:
These 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.
Insights
This study reveals significant gene expression changes in the transforming growth factor beta (TGFβ) pathway in colorectal cancer (CRC), highlighting interactions between genes and microRNAs (miRNAs) that influence CRC progression and patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The transforming growth factor beta (TGFβ) signaling pathway is crucial in colorectal cancer (CRC) pathogenesis.
- Dysregulation and loss-of-function mutations in TGFβ pathway genes, including bone morphogenetic proteins (BMPs), are key events in CRC progression.
Purpose of the Study:
- To comprehensively evaluate differential gene expression within the TGFβ-signaling pathway in CRC.
- To assess the association between dysregulated genes, microRNA (miRNA) expression, and clinical characteristics in CRC patients.
Main Methods:
- RNA sequencing (RNASeq) was used to analyze the expression of 81 TGFβ-signaling pathway genes.
- Agilent Human miRNA Microarray V19.0 was employed to assess miRNA expression in paired carcinoma and normal tissues from 217 CRC cases.
- Statistical analyses were performed to identify differentially expressed genes and miRNAs and their associations with clinical factors like sex, age, disease stage, and survival.
Main Results:
- Thirteen genes were significantly downregulated and 14 were significantly upregulated (FC > 1.50 or < 0.67) in CRC tissues compared to normal tissues.
- Key downregulated genes included BMP5, BMP6, BMP2, and GDF7, while BMP4, BMP7, INHBA, TGFBR1, and others were upregulated.
- Significant associations were found between dysregulated genes and miRNA expression, with some genes showing differential expression patterns in microsatellite-stable (MSS) versus microsatellite-unstable (MSI) tumors.
- Interactions between messenger RNA (mRNA) and miRNA were identified, becoming stronger in advanced disease stages and varying with survival months.
Conclusions:
- The findings support a significant interaction between miRNAs and TGFβ-signaling pathway genes in the context of CRC risk.
- These gene-miRNA interactions are linked to distinct clinical characteristics in CRC, suggesting potential therapeutic targets for future investigation.
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