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Novel tumor suppressor locus in human chromosome region 3p14.2
K Jülicher1, G Marquitan, N Werner
1Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Germany.
Background:
Alterations of chromosome region 3p14 are observed in numerous human malignancies. Because the pattern of allelic losses suggests the existence of at least one tumor suppressor gene within this region, we established a library of yeast artificial chromosomes (YACs) containing contiguous human 3p14 sequences to permit a search for tumor suppressor loci within the 3p14 region by use of functional complementation.
Methods:
YACs specific for human chromosome region 3p14 were transduced by spheroplast fusion into cells of the human nonpapillary renal carcinoma cell line RCC-1, which shows a cytogenetically detectable 3p deletion and is tumorigenic in nude mice.
Results:
We identified a 3p14.2-specific YAC clone, located in the vicinity of the fragile histidine triad (FHIT) gene (but toward the telomere), that is capable of inducing sustained suppression of tumorigenicity in nude mice and of activating cellular senescence in vitro. Among 23 mice given injections of RCC-1 cells containing this YAC, 16 (70%) remained tumor free for at least 6 months, whereas tumor formation occurred after a median of 6 weeks in control mice given injections of either RCC-1 parental cells or a revertant cell line (in which the YAC had lost all human sequences) or RCC-1 parental cells containing other, unrelated YACs. Similar results were obtained following microcell-mediated transfer of the entire human chromosome 3.
Conclusion:
These data provide strong evidence for the existence of a novel tumor suppressor locus adjacent to the previously identified candidate tumor suppressor gene, FHIT, in 3p14.2. Positional cloning of the novel suppressor element within the 3p14.2-specific YAC and the sequence's molecular and functional characterization should add to the understanding of the pathogenesis of renal cell carcinoma and other human tumors that exhibit 3p14 aberrations.
Insights
Researchers identified a novel tumor suppressor locus in chromosome region 3p14.2, adjacent to the FHIT gene, which suppressed tumor formation in renal carcinoma cells and activated cellular senescence, offering new insights into cancer pathogenesis.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Alterations in chromosome region 3p14 are common in human cancers.
- Allelic loss patterns suggest the presence of tumor suppressor genes in 3p14.
- A yeast artificial chromosome (YAC) library was created to identify these genes.
Purpose of the Study:
- To search for tumor suppressor loci within the 3p14 region using functional complementation.
- To identify genes that can suppress tumor formation and induce senescence.
Main Methods:
- Yeast artificial chromosomes (YACs) specific for 3p14 were introduced into renal carcinoma cells (RCC-1).
- The tumorigenicity of modified cells in nude mice and their capacity for cellular senescence in vitro were assessed.
- Microcell-mediated transfer of human chromosome 3 was also performed.
Main Results:
- A 3p14.2-specific YAC clone, near the FHIT gene, suppressed tumor formation in 70% of mice for at least 6 months.
- This YAC also activated cellular senescence in vitro.
- Similar tumor suppression was observed with the transfer of entire human chromosome 3.
Conclusions:
- Strong evidence supports a novel tumor suppressor locus in 3p14.2, adjacent to FHIT.
- Characterization of this locus will enhance understanding of renal cell carcinoma and other 3p14-associated tumors.
- Positional cloning and functional analysis of the suppressor element are warranted.