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Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4
Nicholas R Forsyth1, Vivienne Morrison, Nicola J Craig
1Beatson Institute for Cancer Research, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Abstract:
Squamous cell carcinoma (SCC) immortality is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) of other chromosomes, including chromosome 4. To test for a functional cancer mortality gene on human chromosome 4 we introduced a complete or fragmented copy of the chromosome into SCC lines by microcell-mediated chromosome transfer (MMCT). Human chromosome 4 caused a delayed crisis, specifically in SCC lines with LOH on chromosome 4, but chromosomes 3, 6, 11 and 15 were without effect. The introduction of the telomerase reverse transcriptase into the target lines extended the average telomere terminal fragment length but did not affect the frequency of mortal hybrids following MMCT of chromosome 4. Furthermore, telomerase activity was still present in hybrids displaying the mortal phenotype. The MMCT of chromosomal fragments into BICR6 mapped the mortality gene to between the centromere and 4q23. Deletion analysis of the introduced chromosome in immortal segregants narrowed the candidate interval to 2.7 Mb spanning D4S423 and D4S1557. The results suggest the existence of a gene on human chromosome 4 whose dysfunction contributes to the continuous proliferation of SCC and that this gene operates independently from telomeres, p53 and INK4A.
Insights
A gene on human chromosome 4 can induce mortality in squamous cell carcinoma (SCC) cells, independent of telomerase activity. This discovery offers new insights into SCC immortality and potential therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Cell Biology
Background:
- Squamous cell carcinoma (SCC) immortality is linked to genetic instability, including loss of heterozygosity (LOH) on chromosome 4.
- Key factors in SCC immortality include p53 and INK4A dysfunction and high telomerase levels.
Purpose of the Study:
- To investigate the presence and function of a cancer mortality gene on human chromosome 4.
- To determine if chromosome 4 can induce a crisis in immortal SCC cell lines.
Main Methods:
- Microcell-mediated chromosome transfer (MMCT) was used to introduce human chromosome 4 into SCC lines.
- Telomere length and telomerase activity were analyzed in hybrid cells.
- Chromosomal fragments were used to map the mortality gene locus.
Main Results:
- Introduction of human chromosome 4 induced a delayed crisis in SCC lines with existing LOH on chromosome 4.
- Telomerase introduction did not affect the frequency of cell mortality induced by chromosome 4.
- The mortality gene was localized to a 2.7 Mb interval on chromosome 4 between D4S423 and D4S1557.
Conclusions:
- A gene on human chromosome 4, when functional, can induce mortality in SCC.
- This tumor suppressor gene operates independently of telomere length, telomerase activity, p53, and INK4A.
- Dysfunction of this chromosome 4 gene contributes to SCC continuous proliferation.