K-ras mutations and mucin profile in preneoplastic lesions and colon tumors induced in rats by 1,2-dimethylhydrazine.
K-ras and mucin profile variations, associated with intestinal carcinogenesis, were studied in the preneoplastic lesions, mucin-depleted foci (MDF) and aberrant crypt foci (ACF), and in colonic tumors induced in rats by 1,2-dimethylhydrazine (DMH). The frequency of lesions with K-ras mutations was 23% (3/13), 5.5% (1/18) and 100% (14/14) in MDF, tumors and ACF, respectively. Two of three MDF mutated in K-ras also carried a missense mutation in Apc. We also tested the expression of MUC2, a mucin abundantly expressed in normal colon and M1/MUCA5C, up-regulated in colon carcinogenesis, using immunohistochemistry. MDF and tumors showed a dramatic reduction in the expression of MUC2, whereas ACF showed only a slight reduction. The expression of M1/MUC5AC was almost absent in normal mucosa, but was increased in all the lesions (MDF, tumors and ACF). The expression of the intestinal trefoil factor (ITF), a marker of goblet cell lineage, was reduced in MDF and tumors compared to normal mucosa but not in ACF. In conclusion, although K-ras mutations are present in all ACF, they are less frequent in MDF and tumors; M1/MUC5AC is a marker associated with all preneoplastic events while the reduction of MUC2 and ITF expression is selectively associated with more advanced lesions such as MDF and tumors.
Femia
Angelo Pietro
AP
Department of Pharmacology, University of Florence, Florence, Italy.
Tarquini
Elena
E
Salvadori
Maddalena
M
Ferri
Stefania
S
Giannini
Augusto
A
Dolara
Piero
P
Caderni
Giovanna
G
D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D017491:Genes, APC / Q000502:physiology; D011905:Genes, ras / Q000235:genetics*; D007124:Immunoenzyme Techniques; D008297:Male; D009077:Mucins / Q000172:deficiency*; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000071164:Trefoil Factor-2
D009077:Mucins; D009153:Mutagens; D010455:Peptides; D000071164:Trefoil Factor-2; D019813:1,2-Dimethylhydrazine