Abstract
As the enhanced expression of c-myc protooncogene is specifically associated with human colon cancers and adenomas, this gene may be involved in cancer development in the human colon. The two-stage chemical carcinogenesis model in rats provides a pertinent system to test this hypothesis. Rat colon tumors were produced by 14 daily intrarectal instillations of carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 17μmol), followed by 30 weekly instillations of tumor promoter deoxycholate (12μmol). Tumor incidence was 88% in the 8 rats killed at 33 and 43 weeks. Northern blots of RNAs from the tumors revealed that the levels of c-myc mRNA were 1.8 to 8.4 (mean, 4.2) fold higher than those in the adjacent tissues (15 out of 15 tumors), whereas the amount of c-fos, H-ras, and ornithine decarboxylase mRNAs did not significantly increase in any tumor. The results are in good agreement with those in human colon cancers in that the enhanced expression of c-myc is strongly associated with colon tumors. A single intrarectal instillation of either MNNG or deoxycholate led to a 5-fold increase in the c-myc mRNA level at 3 to 4 hours in the rat colon tissue, the basal level was reverted 6 to 8 hours later.
The effect of deoxycholate was dose dependent; the maximum effect noted at 12 to 48μmol. The same effect was not observed in rat stomach tissue, thereby indicating that enhancement of the c-myc expression by this agent was tissue-specific. It is tempting to speculate that, after repeated stimuli with these agents, some colon cells become capable of expressing c-myc, without exogenous stimulation, hence, acquire the potential to grow tumors.
