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Published on: May 17, 2013
WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite
L Thorstensen1, C B Diep, G I Meling
1Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway.
Background & Aims:
Microsatellite instability (MSI) is the phenotype of colorectal carcinomas with defect mismatch repair. Genes with repetitive sequences within their coding regions are targets for mutations in these tumors. We have evaluated 2 novel candidate genes for potential involvement in development of MSI colorectal carcinomas and compared them with alterations in known target genes.
Methods:
The MSI status was determined by multiplex polymerase chain reactions (PCRs) of 5-17 markers in a Norwegian series of 275 colorectal carcinomas. All MSI tumors were analyzed for gene mutations using fluorescence PCR followed by capillary electrophoresis. Two novel candidate genes, WNT1-inducible signaling pathway protein 3 (WISP-3) and caspase-1, and 9 known target genes were analyzed.
Results:
Thirteen percent of the tumors were MSI-high (H) and 12% were MSI-low (L). Thirty-three of 37 MSI-H vs. 1 of 34 MSI-L tumors showed mutations in the target genes (P < 0.001). WISP-3 was mutated in 31% of the MSI-H tumors. The frequencies of frameshift mutations in the known target genes were comparable with other studies.
Conclusions:
The relative high frequency of mutation, higher than those seen for other known target genes, the predicted truncation of the protein product, and the homology with WISP-1 and WISP-2, 2 proteins induced downstream of WNT1 signaling, strongly suggest WISP-3 as a novel target in development of MSI-H colorectal carcinomas.
Insights
Microsatellite instability-high (MSI-H) colorectal carcinomas frequently harbor mutations in WISP-3, a novel target gene. This finding advances understanding of MSI-H tumor development and potential therapeutic strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Microsatellite instability (MSI) is a hallmark of colorectal carcinomas with deficient mismatch repair.
- Genes with repetitive sequences are prone to mutations in MSI tumors.
- Understanding novel gene targets in MSI colorectal carcinomas is crucial.
Purpose of the Study:
- To investigate the role of two novel candidate genes, WISP-3 and caspase-1, in MSI colorectal carcinomas.
- To compare mutations in these novel genes with known target genes in MSI tumors.
Main Methods:
- Determined MSI status in 275 colorectal carcinomas using multiplex PCR.
- Analyzed MSI tumors for gene mutations using fluorescence PCR and capillary electrophoresis.
- Evaluated WISP-3, caspase-1, and nine known target genes for alterations.
Main Results:
- 13% of tumors were MSI-high (MSI-H) and 12% were MSI-low (MSI-L).
- Mutations in target genes were significantly higher in MSI-H (33/37) versus MSI-L (1/34) tumors.
- WISP-3 was mutated in 31% of MSI-H tumors, a higher frequency than other known targets.
Conclusions:
- WISP-3 mutations are frequent in MSI-H colorectal carcinomas.
- The high mutation rate and predicted protein truncation suggest WISP-3 is a novel target in MSI-H tumor development.
- Findings contribute to understanding the molecular pathogenesis of MSI-H colorectal cancer.
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