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No effects of Smad2 (madh2) null mutation on malignant progression of intestinal polyps in Apc(delta716) knockout
Kazuaki Takaku1, Jeffrey L Wrana, Elizabeth J Robertson
1Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Abstract:
The loss of heterozygosity (LOH) in human chromosome 18q21 is found at high frequencies in advanced pancreatic and colorectal cancers. Several candidate tumor suppressor genes, such as SMAD2, SMAD4, and DCC, are located in this region. The homologues of these genes in the mouse are also clustered on chromosome 18. Mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis, and we earlier constructed a mouse model for familial adenomatous polyposis, Apc(delta716). Although human APC is located on chromosome 5q, mouse Apc is on chromosome 18, 30 cM proximal to the Dcc-Smad4-Smad2 locus. Taking advantage of this fact, we constructed previously a cis-compound Apc(delta716) Smad4 mutant, the intestinal polyps of which progress to very invasive adenocarcinomas. To determine whether Smad2 mutations play similar roles in malignant progression, here we constructed compound mutant mice carrying Apc and Smad2 knockouts in the cis configuration. In contrast to the cis-compound Apc(delta716) Smad4 heterozygotes, the polyps in the cis-compound Apc(delta716) Smad2 heterozygotes showed no difference in the number, size, or histopathology from the polyps in the simple Apc(delta716) heterozygotes. These results suggest that, on human chromosome 18q21, the SMAD4 LOH plays a more significant role, and SMAD2 LOH is insufficient to cause malignant progression of colonic polyps.
Insights
Loss of heterozygosity in chromosome 18q21 is common in advanced cancers. SMAD4 loss significantly impacts malignant progression, while SMAD2 loss alone is insufficient for colonic polyp advancement.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Loss of heterozygosity (LOH) at human chromosome 18q21 is frequent in advanced pancreatic and colorectal cancers.
- Candidate tumor suppressor genes like SMAD2 and SMAD4 are located in this critical region.
- Mouse Apc gene is located on chromosome 18, proximal to the Dcc-Smad4-Smad2 locus.
Purpose of the Study:
- To investigate the role of Smad2 mutations in malignant progression of colonic polyps.
- To compare the effect of Smad2 versus Smad4 loss in conjunction with Apc mutations.
Main Methods:
- Construction of cis-compound mutant mice with Apc and Smad2 knockouts.
- Analysis of polyp number, size, and histopathology in Apc(delta716)Smad2 heterozygotes.
- Comparison with Apc(delta716)Smad4 heterozygotes and simple Apc(delta716) heterozygotes.
Main Results:
- Apc(delta716)Smad2 heterozygotes showed no significant difference in polyp characteristics compared to Apc(delta716) heterozygotes.
- In contrast, previous studies showed Apc(delta716)Smad4 heterozygotes developed invasive adenocarcinomas.
- These findings indicate Smad2 LOH is insufficient for malignant progression in this model.
Conclusions:
- SMAD4 LOH plays a more significant role in the malignant progression of colonic polyps than SMAD2 LOH.
- SMAD2 LOH alone is insufficient to drive the progression of colonic polyps to invasive adenocarcinomas.
- The study highlights the differential roles of SMAD4 and SMAD2 in cancer development on chromosome 18q21.