Somatic Acquisition and Signaling of &lt;EMPH TYPE="ITAL"&gt;TGFBR1&lt;/EMPH&gt;*6A in Cancer

Pasche, Boris; Knobloch, Thomas J.; Bian, Yansong; Liu, Junjian; Phukan, Sharbani; Rosman, Diana S.; Kaklamani, Virginia; Baddi, Lisa; Siddiqui, Farida; Frankel, Wendy L.; Prior, Thomas W.; Schuller, David E.; Agrawal, Amit; Lang, Jas C.; Dolan, M. Eileen; Vokes, Everett E.; Lane, William S.; Huang, Chiang Ching; Caldés, Trinidad; Cristofano, Antonio Di; Hampel, Heather; Im, Nilsson; Heijne, Gunnar von; Fodde, Riccardo; Murty, V. V. V. S.; Chapelle, Albert de la; Weghorst, Christopher M.

doi:10.1001/jama.294.13.1634

Cited by 89 publications

(115 citation statements)

References 54 publications

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“…31 Despite the growth suppression observed in our ACVR2-restored cellular models, activin enhances cellular motility. Our finding is congruent with the fact that migration of normal colon epithelial cells is enhanced by TGF-β 32 and with the recent observation of somatic acquisition of activating mutations in TGFBR1 in metastases and not from the source of primary colon cancers, 33 as well as worse survival with wild-type TGFBR2 in patients with MSI-H colon cancers. 34 Additionally, the non-invasive activin-sensitive colon cancer cell line FET did not show enhanced migration with activin treatment (data not shown), while the complemented HCT116+chr2 colon cancer cells, which are invasive, 35 did.…”

Section: Discussionsupporting

confidence: 91%

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

et al. 2007

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Background & Aims-Colon cancers with high-frequency microsatellite instability (MSI-H) develop frameshift mutations in tumor suppressors as part of their pathogenesis. ACVR2 is mutated at its exon 10 polyadenine tract in >80% of MSI-H colon cancers, coinciding with loss of protein. ACVR2 transmits the growth effects of activin via phosphorylation of SMAD proteins to affect gene transcription. The functional effect of activin in colon cancers has not been studied. We developed and characterized a cell model in which we studied how activin signaling affects growth.

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Section: Discussionsupporting

confidence: 91%

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

et al. 2007

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“…This allele may be extremely important not only when present in the germ line, but also as a somatically acquired change highly associated with CRC metastases to the liver. 23 Recently, it was proposed that the well-known polymorphism in codon 72 of the TP53 gene has a profound effect on the age of onset of CRC in Lynch syndrome, 24 and the findings were confirmed by Kruger et al 25 However, in a third study, 26 no such effect was seen. This illustrates the fact that genetic association studies are, especially whenever the studied effect is relatively subtle, difficult to interpret and often contradictory.…”

Section: Modifier Genesmentioning

confidence: 93%

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

et al. 2006

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“…TGFBR1*6A is a common polymorphic variant of the TGF-β receptor I gene, and an association between TGFBR1*6A and human colorectal cancer has previously been reported (23). Studies conducted by Pasche et al (23) revealed that there is a significantly higher TGFBR1*6A allelic frequency in patients with colorectal cancer than in healthy controls. Furthermore, TGFBR1*6A was somatically acquired during colorectal cancer tumorigenesis and liver metastasis (15).…”

Section: Discussionmentioning

confidence: 99%

“…The optical density (OD) 260/OD 280 of the DNA used for PCR amplification was ~1.80. The TGFBR1 exon 1 coding sequence was as previously described, and PCR amplification was also performed as previously described (23). PCR was performed using Advantage-GC Genomic Polymerase Mix (Invitrogen; Thermo Fisher Scientific, Inc.) in a total volume of 25 ml containing 50 ng DNA and 1.25 U Platinum Taq DNA polymerase (Invitrogen; Thermo Fisher Scientific, Inc.).…”

Section: Dna Extraction and Polymerase Chain Reaction (Pcr)mentioning

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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Somatic Acquisition and Signaling of <EMPH TYPE="ITAL">TGFBR1</EMPH>*6A in Cancer

Cited by 89 publications

References 54 publications

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

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

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