Transforming Growth Factor β Superfamily Signaling in Development of Colorectal Cancer

Jung, Barbara; Staudacher, Jonas J.; Beauchamp, Daniel

doi:10.1053/j.gastro.2016.10.015

Cited by 202 publications

(159 citation statements)

References 185 publications

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“…Increasing evidence has suggested that signaling pathways such as WNT/β-catenin and TGFβ/SMAD pathways may be involved in modulating tumorigenesis [33, 34]. Among these pathways, activation of TGFβ/SMAD plays an important role in enhancing the EMT to remodel the prometastasis phenotype [11], and SNAIL family members are regulated by the TGFβ/SMAD signaling pathway [22]. Thus, we confirmed the expression of proteins critical in the TGFβ/SMAD pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, several transcriptional factors strongly repress CDH1 transcription such as members of Snail, Zeb, and basic-helix-loop-helix (bHLH) families [22]. The TGFβ/SMAD signaling pathway plays an important role in a complicated signaling network, which coordinates the expression of Slug, Zeb, and bHLH families to promote tumor progression and enhance the EMT [11]. However, the detailed mechanisms underlying the EMT are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…TGF-β is a secreted protein that activates canonical pathways, including SMAD2, SMAD3, and SMAD4, and non-canonical pathways, including phosphoinositide 3-kinase/Akt, mitogen-activated protein kinase-extracellular signal-regulated kinase, and c-Jun N-terminal kinase [11]. The role of TGF-β is paradoxical due to its tumor suppressor and oncogenic activities [12].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

Hu¹,

Wang²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Colorectal cancer (CRC) is a malignancy that has high morbidity and mortality and is initiated from accumulative genetic events. Although much effort has been made to elucidate the genetic mechanism underlying this disease, it still remains unknown. Here, we discovered a novel role for multiple epidermal growth factor-like domains protein 6 (MEGF6) in CRC, namely, that it induces the epithelial-to-mesenchymal transition (EMT) to promote CRC metastasis via the transforming growth factor beta (TGFβ)/SMAD signaling pathway. Methods: RNA sequencing data from the Gene Expression Omnibus database were analyzed using R software. Based on The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort, the clinical significance of MEGF6 was investigated. HCT8R, HCT116, and LoVo CRC cells were transfected with small interfering RNA against MEGF6, and their proliferation and sensitivity to fluorouracil were evaluated with the MTT cell proliferation and colony formation assays. Proteins associated with cell growth were detected by western blot analysis. The apoptosis of cells was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess the involvement of MEGF6 in cell migration. Markers of EMT and TGFβ/SMAD signaling were evaluated by quantitative PCR and western blotting, and the correlation between MEGF6 and these markers was assessed in the TCGA colon and renal adenocarcinoma cohort. Results: The results showed that MEGF6 was upregulated in HCT8R cells. In addition, MEGF6 was significantly overexpressed in tumor tissue and predicted a poor survival in the TCGA-COAD cohort. Moreover, MEGF6 accelerated CRC cell growth and inhibited apoptosis, and promoted CRC metastasis by inducing the EMT. Finally, we found that TGFβ/SMAD signaling triggered the expression of Slug, which regulates the MEGF6-mediated EMT. Conclusions: MEGF6 may serve as an oncogene to promote cell proliferation and inhibit apoptosis. MEGF6 can also accelerate cell migration via TGFβ/SMAD signaling-mediated EMT.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

Hu¹,

Wang²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…TGFBR1*6A, a common allele located at exon 1 of the TGFBR1 gene, has been reported to act as a low-penetrance tumor-susceptibility allele in human colorectal cancer cell lines. It is also less effective at transducing TGF-β signaling compared with the TGFBR1*9A wild type (10). Functional studies have demonstrated that the TGFBR1*6A allele is associated with an increased risk of various different malignancies, including breast cancer and osteosarcoma (11).…”

Section: Introductionmentioning

confidence: 99%

TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells

et al. 2018

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Abstract. Type 1 transforming growth factor β receptor (TGFBR1)*6A, a common hypomorphic variant of TGFBR1, may act as a susceptibility allele in colorectal cancer. However, the contribution of TGFBR1*6A to colorectal cancer development is largely unknown. To test the hypothesis that TGFBR1*6A promotes colorectal cancer invasion and metastasis via Smad-independent transforming growth factor-β (TGF-β) signaling, the effect of TGFBR1*6A on the invasion of colorectal cancer cells was assessed. pCMV5-TGFBR1*6A-HA plasmids were transfected into SW48 and DLD-1 cells by Lipofectamine-mediated DNA transfection. The effect of TGF-β1 on the proliferation of SW48 and DLD-1 cells transfected with TGFBR1*6A was determined by MTT assay. The effects of the TGF-β1 on the invasion of the transfected SW48 and DLD-1 cells were determined using Matrigel-coated plates. Transforming migrating chambers were used to determine the effects of TGF-β1 on the migration of the transfected SW48 and DLD-1 cells. Western blot analysis was used to determine the expression of phosphorylated (p-) extracellular-signal-regulated kinase (ERK), p-P38 and p-SMAD family member 2 in SW48 cells. Using transfected TGFBR1*6A SW48 and DLD-1 cell lines our group demonstrated that, in comparison with TGFBR1*9A, TGFBR1*6A is capable of switching TGF-β1 growth-inhibitory signals into growth-stimulatory signals which significantly increased the invasion of SW48 and DLD-1 cells. Functional assays indicated that TGFBR1*6A weakened Smad-signaling but increased ERK and p38 signaling, which are crucial mediators of cell migration and invasion. From this, it was possible to conclude that TGFBR1*6A enhanced SW48 cell migration and invasion through the mitogen-activated protein kinase pathway and that it may contribute to colorectal cancer progression in a TGF-β1/Smad signaling-independent manner. This suggests that TGFBR1*6A may possess oncogenic properties and that it may affect the migration and invasion of colorectal cancer cells.

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“…Two major physiologic inhibitors are known, the competitive antagonist inhibin 9 and the specific ligand trap follistatin 10,11 . First described as a reproductive hormone upstream of follicle-stimulating hormone (FSH) 12 , subsequent studies showed substantial roles in such diverse contexts as embryogenesis 13 , cancer 8,14,15 , and inflammation 16 . In inflammation, activin has been reported to have both pro-and anti-inflammatory functions ex vivo, resulting in either up-or down-regulation of a number of key inflammatory cytokines, such as IL-6, IL-1-β or IL10 in a spectrum of human and murine cell types [17][18][19][20] .…”

mentioning

confidence: 99%

Activin in Acute Pancreatitis: Potential Risk-Stratifying Marker and Novel Therapeutic Target

Staudacher¹,

Yazıcı²,

Carroll³

et al. 2017

Gastroenterology

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Transforming Growth Factor β Superfamily Signaling in Development of Colorectal Cancer

Cited by 202 publications

References 185 publications

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells

Activin in Acute Pancreatitis: Potential Risk-Stratifying Marker and Novel Therapeutic Target

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