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C3H mouse embryo cells, which normally have low inherent spontaneous transformation, underwent malignant transformation while chronically infected with Mycoplasma fermentans or Mycoplasma penetrans. This mycoplasma-mediated oncogenic process had long latency (more than 7 weeks of persistent mycoplasmal infection) and showed multistage progression characterized by reversibility and irreversibility of malignant properties upon removal of M. fermentans from culture. Marked expression of H-ras and c-myc mRNA, but not N-myc, src, N-ras, or p53 mRNA, was found in the mycoplasma-transformed C3H cells that exhibited characteristic malignant properties of morphological changes and uncontrolled cell growth. However, at least up to the eleventh week of persistent mycoplasma infection, the marked expression of H-ras or c-myc mRNA in C3H cells depended on continued presence of the mycoplasma in culture. H-ras or c-myc mRNA rapidly declined to the undetectable low levels of nontransformed parental C3H cells, and all malignant properties of the once-fully-transformed C3H cells quickly reversed, if M. fermentans was eradicated from culture. In comparison, infection with M. penetrans for 7 or 11 weeks also induced a high level of H-ras, but not c-myc, mRNA expression in C3H cells. Despite having prominent amount of steady-state H-ras mRNA, these M. penetrans-infected C3H cells did not show any sign of malignant transformation. Thus, marked expression of H-ras gene alone was not sufficient to effect transformation in C3H cells. Interestingly, after a further prolonged (18 weeks) infection with either M. fermentans or M. penetrans, C3H cells revealed prominent chromosomal changes, expressed constitutively (with or without the presence of the transforming mycoplasmas) at high levels of both H-ras and c-myc mRNA and became permanently transformed. These cells were able to form tumors in animals.