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

Abstract

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.

Signaling pathways involved in colorectal cancer progression

“…Identified mutations in TGFBR1 in CRC cell lines are not common [50]. TGFBR1*6A, a polymorphic allele of TGFBR1 , was detected in the TGFBR1 tumor-specific mutations [51]. TGFBR1*6A has been associated with a 24% increase in the risk of CRC [28, 51].…”

“…TGFBR1*6A, a polymorphic allele of TGFBR1 , was detected in the TGFBR1 tumor-specific mutations [51]. TGFBR1*6A has been associated with a 24% increase in the risk of CRC [28, 51]. It is speculated that TGFBR1*6A may cause switching of TGF-β growth inhibitory signals to the growth stimulatory ones, thereby contributing to tumorigenesis [51].…”

The Role of TGF-β and Its Receptors in Gastrointestinal Cancers

“…For example, loss of three alanine residues within a stretch of nine alanine residues in the N-terminal region of TβRI (TGFBR1*6A) was associated with an increased risk of CRC [122], though these results have not been confirmed [123]. However, a recent study pointed out an oncogenic property of TGFBR1*6A which may promote the migration and invasion of colorectal cancer cells [124].…”

Prognostic value of transforming growth factor beta receptor 1 polymorphisms in patients with oral cancer

“…Experimental studies have shown that TGFBR1 can promote malignant proliferation and metastasis of tumors by regulating epithelial‐mesenchymal transformation . Rosman et al and Zhou et al also revealed similar outcomes that TGFBR1*6A could promote the invasion and metastasis of MCF‑7 breast cancer cells and colorectal cancer cells. Moreover, Nicoloso et al demonstrated that GG genotype of rs334348 was associated with lower TGFBR1 expression .…”

“…This pathway is vital in the development and progression of malignancy by regulating cellular proliferation and differentiation . Previous researches have shown that genetic polymorphism and aberrant expression of TGFBR1 were associated with prognosis of several digestive tract cancers, including gastric cancer and colorectal cancer . Additionally, a recent study also demonstrated that higher TGFBR1 expression may represent poor prognosis in advanced head and neck squamous cell carcinomas (HNSCC) .…”