Possible role of activated ras genes in human esophageal carcinogenesis.
Activation by point mutation of the H-, K- and N-ras genes is found in many tumors. However, no such mutation has yet been found in human esophageal carcinomas from various parts of the world. We have confirmed the absence of mutation at codons 12, 13 and 61 of K- and N-ras and at codons 12 and 61 of H-ras in 25 primary tumors obtained in France. In contrast, among 7 human esophageal carcinoma cell lines (TE1, TE2, TE3, TE8, TE9, TE10, TE13) with different degrees of tumorigenicity in nude mice, 3 highly tumorigenic lines (TE1, TE2 and TE8) exhibited activation of ras oncogenes; 2 showed a G35 to A35 transition of K-ras gene and one a H-ras G35 to T35 transversion. Since these cell lines had been established from tumors of Japanese patients from Sendai, we examined 3 primary esophageal tumors from Tokyo and 19 from Sendai, including the primary tumors from which the TE cell lines had been derived. No ras mutation was detected, which suggests that the ras gene mutations in the TE cell lines are either due to their long-term culture or that only a small portion of the original tumors contained such mutations. In order to directly examine the effect of ras gene mutation, one of the non-tumorigenic cell lines, TE13, was transfected with a plasmid coding for a mutated H-ras gene (G35 to T35). Transfected clones expressing high levels of mutated ras gene were able to induce tumors in nude mice. Thus, although no primary human esophageal tumor contained mutated ras genes, our studies do not exclude a significant role of mutated ras genes in cell proliferation and malignant transformation of human esophageal cells.
Galiana
C
C
Unit of Multistage Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Fusco
A
A
Martel
N
N
Nishihira
T
T
Hirohashi
S
S
Yamasaki
H
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004938:Esophageal Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D014162:Transfection