Related Experiment Video
Updated: Jun 26, 2026
Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform
Published on: May 10, 2024
Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development
Qinghua Zeng1, Sharbani Phukan, Yanfei Xu
1Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Abstract:
Transforming growth factor-beta (TGF-beta) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with Apc(Min/+) mice, we show that Apc(Min/+);Tgfbr1(+/-) mice develop twice as many intestinal tumors as Apc(Min/+);Tgfbr1(+/+) mice, as well as adenocarcinoma of the colon, without loss of heterozygosity at the Tgfbr1 locus. Decreased Smad2 and Smad3 phosphorylation and increased cellular proliferation are observed in the colonic epithelium crypts of Apc(Min/+); Tgfbr1(+/-) mice. Smad-mediated TGF-beta signaling is preserved in both Apc(Min/+);Tgfbr1(+/+) and Apc(Min/+);Tgfbr1(+/-) intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in Apc(Min/+);Tgfbr1(+/-) tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-beta signaling significantly enhances colorectal cancer development and results in increased tumor cell proliferation. These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer.
Insights
Reduced transforming growth factor-beta 1 receptor (TGFBR1) signaling significantly increases colorectal cancer development and tumor cell proliferation in mice. This suggests a molecular mechanism for cancer in individuals with altered TGFBR1 expression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Transforming growth factor-beta (TGF-beta) signaling pathways are frequently dysregulated in colorectal cancer.
- Alterations in TGF-beta signaling components, including TGFBR1, are implicated in cancer progression.
Purpose of the Study:
- To investigate the role of reduced TGFBR1 expression in colorectal cancer development using a novel mouse model.
- To elucidate the molecular mechanisms by which diminished TGF-beta signaling impacts tumor initiation and progression.
Main Methods:
- Generation of a novel mouse model by crossing Tgfbr1 heterozygous mice with Apc(Min/+) mice.
- Analysis of intestinal tumor development, histopathology, and molecular markers (Smad phosphorylation, cyclin D1 expression, cellular proliferation) in the resulting mouse cohorts.
- Assessment of Tgfbr1 locus integrity in tumor tissues.
Main Results:
- Apc(Min/+);Tgfbr1(+/-) mice exhibited a twofold increase in intestinal tumors compared to controls, including colon adenocarcinoma.
- Reduced Smad2/3 phosphorylation and increased epithelial cell proliferation were observed in the colonic crypts of Tgfbr1(+/-) mice.
- Despite preserved Smad-mediated signaling in tumors, Apc(Min/+);Tgfbr1(+/-) tumors showed significantly higher cyclin D1 expression and proliferation.
Conclusions:
- Constitutively reduced Tgfbr1-mediated TGF-beta signaling significantly promotes colorectal cancer development.
- Diminished TGFBR1 signaling enhances tumor cell proliferation, potentially through mechanisms involving cyclin D1.
- These findings offer a molecular explanation for colorectal cancer in individuals with altered TGFBR1 expression.
Related Concept Videos
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...