Abstract
Metallothionein (MT) overexpression occurs frequently in human tumours but the underlying mechanism is unknown. Morphologically normal-appearing mucosa from human colorectal carcinoma resection specimens and of the colons of ageing laboratory mice contains scattered single crypts whose cells show uniformly increased MT immunostaining, suggesting that MT overexpression arises directly from random crypt stem cell somatic mutation, followed by colonization of the clonal unit by the mutated progeny. This hypothesis has now been tested by quantifying the frequency of immunocytochemically detectable monocryptal colorectal MT overexpression, 5 and 30 days after injection of 8-week-old mice with a single dose of the mutagen dimethylhydrazine (DMH, 30 mg/kg subcutaneous). Otherwise normal-appearing MT-positive crypts were recorded as either wholly or partially involved by the overexpressing phenotype. Five days after DMH injection, the median frequency of partially involved MT-positive crypts was 11.7 x 10-4, declining significantly to 1.8 x 10-4 at 30 days (Mann-Whitney U, P-4 at 5 days, increasing significantly (P-4 at 30 days. The frequency of MT-positive crypts and the time course of evolution of partially involved to wholly involved forms were similar to those described for mutation-induced crypt-restricted loss of glucose-6-phosphate dehydrogenase activity in mice treated with an identical DMH regimen. The findings indicate that cellular MT overexpression can occur as a direct consequence of somatic mutation, either cis-activating mutation(s) of the MT gene itself, or trans-activating mutation(s) of other genes involved in controlling MT expression. This is likely to be an important mechanism underlying MT overexpression in neoplasia. Such mutation-induced aberrant MT expression may be involved in the acquisition of selective cellular growth or survival advantage during tumour progression.
| Original language | English |
|---|---|
| Pages (from-to) | 144-147 |
| Number of pages | 4 |
| Journal | Journal of Pathology |
| Volume | 184 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1998 |
| Externally published | Yes |
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Keywords
- Clonality
- Colon
- Gene expression
- Human
- Metallothionein
- Mouse
- Mutation
- Neoplasia
ASJC Scopus subject areas
- Pathology and Forensic Medicine
Cite this
Clonal overexpression of metallothionein is induced by somatic mutation in morphologically normal colonic mucosa. / Jasani, Bharat; Campbell, Fiona; Navabi, Hossein; Schmid, Kurt W.; Williams, Geraint T.
In: Journal of Pathology, Vol. 184, No. 2, 1998, p. 144-147.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Clonal overexpression of metallothionein is induced by somatic mutation in morphologically normal colonic mucosa
AU - Jasani, Bharat
AU - Campbell, Fiona
AU - Navabi, Hossein
AU - Schmid, Kurt W.
AU - Williams, Geraint T.
PY - 1998
Y1 - 1998
N2 - Metallothionein (MT) overexpression occurs frequently in human tumours but the underlying mechanism is unknown. Morphologically normal-appearing mucosa from human colorectal carcinoma resection specimens and of the colons of ageing laboratory mice contains scattered single crypts whose cells show uniformly increased MT immunostaining, suggesting that MT overexpression arises directly from random crypt stem cell somatic mutation, followed by colonization of the clonal unit by the mutated progeny. This hypothesis has now been tested by quantifying the frequency of immunocytochemically detectable monocryptal colorectal MT overexpression, 5 and 30 days after injection of 8-week-old mice with a single dose of the mutagen dimethylhydrazine (DMH, 30 mg/kg subcutaneous). Otherwise normal-appearing MT-positive crypts were recorded as either wholly or partially involved by the overexpressing phenotype. Five days after DMH injection, the median frequency of partially involved MT-positive crypts was 11.7 x 10-4, declining significantly to 1.8 x 10-4 at 30 days (Mann-Whitney U, P-4 at 5 days, increasing significantly (P-4 at 30 days. The frequency of MT-positive crypts and the time course of evolution of partially involved to wholly involved forms were similar to those described for mutation-induced crypt-restricted loss of glucose-6-phosphate dehydrogenase activity in mice treated with an identical DMH regimen. The findings indicate that cellular MT overexpression can occur as a direct consequence of somatic mutation, either cis-activating mutation(s) of the MT gene itself, or trans-activating mutation(s) of other genes involved in controlling MT expression. This is likely to be an important mechanism underlying MT overexpression in neoplasia. Such mutation-induced aberrant MT expression may be involved in the acquisition of selective cellular growth or survival advantage during tumour progression.
AB - Metallothionein (MT) overexpression occurs frequently in human tumours but the underlying mechanism is unknown. Morphologically normal-appearing mucosa from human colorectal carcinoma resection specimens and of the colons of ageing laboratory mice contains scattered single crypts whose cells show uniformly increased MT immunostaining, suggesting that MT overexpression arises directly from random crypt stem cell somatic mutation, followed by colonization of the clonal unit by the mutated progeny. This hypothesis has now been tested by quantifying the frequency of immunocytochemically detectable monocryptal colorectal MT overexpression, 5 and 30 days after injection of 8-week-old mice with a single dose of the mutagen dimethylhydrazine (DMH, 30 mg/kg subcutaneous). Otherwise normal-appearing MT-positive crypts were recorded as either wholly or partially involved by the overexpressing phenotype. Five days after DMH injection, the median frequency of partially involved MT-positive crypts was 11.7 x 10-4, declining significantly to 1.8 x 10-4 at 30 days (Mann-Whitney U, P-4 at 5 days, increasing significantly (P-4 at 30 days. The frequency of MT-positive crypts and the time course of evolution of partially involved to wholly involved forms were similar to those described for mutation-induced crypt-restricted loss of glucose-6-phosphate dehydrogenase activity in mice treated with an identical DMH regimen. The findings indicate that cellular MT overexpression can occur as a direct consequence of somatic mutation, either cis-activating mutation(s) of the MT gene itself, or trans-activating mutation(s) of other genes involved in controlling MT expression. This is likely to be an important mechanism underlying MT overexpression in neoplasia. Such mutation-induced aberrant MT expression may be involved in the acquisition of selective cellular growth or survival advantage during tumour progression.
KW - Clonality
KW - Colon
KW - Gene expression
KW - Human
KW - Metallothionein
KW - Mouse
KW - Mutation
KW - Neoplasia
UR - http://www.scopus.com/inward/record.url?scp=0031911745&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031911745&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1096-9896(199802)184:2<144::AID-PATH998>3.0.CO;2-J
DO - 10.1002/(SICI)1096-9896(199802)184:2<144::AID-PATH998>3.0.CO;2-J
M3 - Article
C2 - 9602704
AN - SCOPUS:0031911745
VL - 184
SP - 144
EP - 147
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 2
ER -