Genetic variants in the TGFβ-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue

Slattery, Martha L.; Trivellas, Andromahi; Pellatt, Andrew J.; Mullany, Lila E.; Stevens, John R.; Wolff, Roger K.; Herrick, Jennifer S.

doi:10.18632/oncotarget.14508

Cited by 27 publications

(23 citation statements)

References 47 publications

(63 reference statements)

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“… 23 Additionally, this signaling pathway is also involved in both angiogenesis and inflammation. 24 The TGF-β signaling pathway has the ability to mediate the intracellular actions of proinflammatory cytokines, including the activation of nuclear factor-kappa B (NFκB). Deficiency in TGF-β has been witnessed in the progression of extensive inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

RETRACTION: Mechanism of MicroRNA-708 Targeting BAMBI in Cell Proliferation, Migration, and Apoptosis in Mice With Melanoma via the Wnt and TGF-β Signaling Pathways

Yan

Jin

et al. 2018

Technol Cancer Res Treat

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Objective:The aim of this study was to evaluate the mechanisms involved with miRNA-708 and its targeting of bone morphogenetic protein and activin membrane-bound inhibitor in cell proliferation, migration, and apoptosis in mice with melanoma via the Wnt and transforming growth factor β signaling pathways.Methods:Sixty mice were recruited of which 40 were subsequently assigned into the experimental group (22 mice were successfully established as melanoma model and 18 mice used in tumor xenograft), and the normal control group consisted of 20 mice. B16 cells were assigned to the normal, blank, and negative control, miR-708 mimics, miR-708 inhibitors, si-BAMBI, and miR-708 inhibitors + si-bone morphogenetic protein and activin membrane-bound inhibitor groups. Western blotting and reverse transcription quantitative polymerase chain reaction were employed to detect the expression levels within the tissues and cell lines. TCF luciferase reporter (TOP-FLASH) or a control vector (FOP-FLASH) was applied to detect the activity of the Wnt signaling pathway. MTT3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, flow cytometry, scratch test, and Transwell assay were conducted, respectively, for cell proliferation, apoptosis, migration, and invasion, while tumor xenograft procedures were performed on the nude mice recruited for the study.Results:Compared to the normal control group, the model group displayed increased expressions of bone morphogenetic protein and activin membrane-bound inhibitor, Wnt10B, P53, and Bcl-2; TOPflash activity; β-catenin expression; cell proliferation; migration; and invasion capabilities while decreased expressions of miR-708, vascular endothelial growth factor, Fas, Bax, Caspase-3, and cleaved Caspase-3 and apoptosis rate. Compared to the blank and negative control groups, the miR-708 mimics and small-interfering RNA-bone morphogenetic protein and activin membrane-bound inhibitor groups exhibited decreases expressions of bone morphogenetic protein and activin membrane-bound inhibitor, Wnt10B, P53, and Bcl-2 and decreased proliferation, migration, and invasion capabilities, while increases in the apoptosis rate, expressions of vascular endothelial growth factor, Fas, Bax, Caspase-3, and cleaved Caspase-3; however, downregulated levels of TOPflash activity and β-catenin expression were recorded. The miR-708 inhibitors group displayed an opposite trend.Conclusion:Downregulation of miR-708-targeted bone morphogenetic protein and activin membrane-bound inhibitor inhibits the proliferation and migration of melanoma cells through the activation of the transforming growth factor β pathway and the suppression of Wnt pathway.

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Section: Discussionmentioning

confidence: 99%

RETRACTION: Mechanism of MicroRNA-708 Targeting BAMBI in Cell Proliferation, Migration, and Apoptosis in Mice With Melanoma via the Wnt and TGF-β Signaling Pathways

Yan

Jin

et al. 2018

Technol Cancer Res Treat

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“…Although the TGFβ-signaling pathway appears to be important for CRC, few studies have looked at this pathway with miRNAs. We have previously examined miRNA expression with SNPs in 21 genes associated with the TGFβ-signaling pathway and found that expression of several miRNAs varied by SNPs in TGFβ1 in normal mucosa [ 32 ]. Additionally, other groups have found that specific miRNAs play a significant role in CRC via the TGFβ pathway.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…It has been demonstrated that C‐509T polymorphism is significantly associated with a higher plasma concentration of TGFB1 . In addition, there was a significant correlation between the TGFB1 (rs4803455) mRNA expression and normal colorectal mucosa, supporting the notion of transforming growth factor beta signaling pathway involvement in carcinogenic process of colorectal cancer . Previous findings in patients with high myopia also showed that rs4803455, tag SNP in intron 2 suggested a functional effect for genuine causative variants in linkage disequilibrium in TGFB1 …”

Section: Discussionmentioning

confidence: 77%

“…27,28 In addition, there was a significant correlation between the TGFB1 (rs4803455) mRNA expression and normal colorectal mucosa, supporting the notion of transforming growth factor beta signaling pathway involvement in carcinogenic process of colorectal cancer. 29 Previous findings in patients with high myopia also showed that rs4803455, tag SNP in intron 2 suggested a functional effect for genuine causative variants in linkage disequilibrium in TGFB1. 30 Previously, we had published a trend of increased gastric TGFB1 mRNA expression in patients with FD (P = .09) and showed negative association with HADS compared to healthy individuals.…”

Section: Discussionmentioning

confidence: 96%

Functional dyspepsia susceptibility is associated with TGFB1 gene polymorphisms (RS4803455, RS1800469) in H pylori‐negative Chinese population

Cheung

Lin

Chan

et al. 2019

Neurogastroenterology Motil

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Background We previously published that altered expression of gastric TRPV1, BDNF, and peripheral cytokines was present in patients with functional dyspepsia. We herein examine whether genetic predisposition in altered biomarkers influences dyspeptic, sleep, and mood symptoms in patients with FD without previous infection. Methods Consecutive adult FD patients (Rome III) with no recent history of gastroenteritis and asymptomatic age‐ and sex‐matched healthy controls were recruited for upper endoscopy. Subjects with GERD and IBS as predominant symptoms, diabetes mellitus, current or previous H pylori infection, psychiatric illness, and recent use of NSAID or PPI were excluded. The genetic associations with dyspeptic symptoms, sleep quality, and mood symptoms were evaluated. Genetic polymorphisms in TRPV1, TGFB1, TNF, COMT, BDNF, IL6, IL8, IL10, and IL12 were analyzed. Key results Twenty‐nine male FD patients and 104 female FD patients were age matched (±3 years) with 81 healthy subjects. All had postprandial distress syndrome (PDS) as predominant subtype (PDS: 130, EPS: 3). SNPs in TGFB1 showed significant associations in dyspeptic patients after age and sex adjustment [for RS4803455: in the codominant model (C/A, OR = 0.34 (0.18‐0.65), P = .004); in the dominant model (genotype C/C vs C/A‐A/A, OR = 0.42 (0.23‐0.77), P = .004); and in the overdominant model (genotype C/C‐A/A vs C/A, OR = 0.38 (0.21‐0.70), P < .001)] [for RS1800469: in dominant model (genotype A/A vs A/G‐G/G, OR = 0.52 (0.27‐0.99), P = .043)]. A allele in RS4803455 was associated with higher HADS depression score (P = .05) and epigastric burning sensation(P = .01). Conclusions and inferences Our data showed that dyspeptic patients predispose genetic difference in TGFB1 which may influence the severity of dyspepsia.

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Genetic variants in the TGFβ-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue

Cited by 27 publications

References 47 publications

RETRACTION: Mechanism of MicroRNA-708 Targeting BAMBI in Cell Proliferation, Migration, and Apoptosis in Mice With Melanoma via the Wnt and TGF-β Signaling Pathways

RETRACTION: Mechanism of MicroRNA-708 Targeting BAMBI in Cell Proliferation, Migration, and Apoptosis in Mice With Melanoma via the Wnt and TGF-β Signaling Pathways

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

Functional dyspepsia susceptibility is associated with TGFB1 gene polymorphisms (RS4803455, RS1800469) in H pylori‐negative Chinese population

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