The effects of colectomy on immediate-early proto-oncogene expression and hepatic regeneration in the rat.

ABSTRACT

The intact liver exists in a state of replicative quiescence. The factor(s) responsible for maintaining this state and their tissue sources have yet to be identified. Because the colon synthesizes and/or absorbs numerous agents that inhibit hepatocyte proliferation, the principle purpose of this study was to determine whether total colectomy would result in the conversion of quiescent livers to a state of replicative competence. Thus, adult, male Sprague-Dawley rats (250-300 g) were randomized to undergo either total colectomy with ileostomy or sham surgery. Thereafter, rats were sacrificed (N=3-6/group) at times 15 and 30 min and 1, 2, 6, and 24 hr and the livers analyzed by Northern blot analyses for mRNA of the following immediate-early proto-oncogenes (IEP genes) c-fos, c-jun, and c-myc. Rats sacrificed at 24 hr also had hepatic regenerative activity documented by [3H]thymidine incorporation into hepatic DNA. The results of the study revealed that within 15 min, c-fos and c-jun mRNA expression increased in colectomized rats, with peak expression occurring at 30 and 60 min, respectively. c-myc mRNA expression was more delayed, with peak expression occurring at 6 hr post-colectomy. IEP gene expression also increased somewhat in sham-colectomy controls but the increases were not as prompt and, in general, were of lower magnitude than those in the colectomy group. Despite the differences in IEP gene expression between the two groups, [3H]thymidine incorporation at 24 hr was similar (mean+/-SE colectomy group, 17.2+/-2.6 dpm/microg DNA; sham-colectomy controls, 14.8+/-1.4 dpm/microg DNA). To determine whether the increases in IEP gene expression expedite or augment the hepatic regenerative response to partial hepatectomy (PHx), rats that had undergone colectomy or sham colectomy 1 hr earlier and rats with no previous abdominal surgery then underwent a 70% PHx and were sacrificed at 8, 16, and 24 hr thereafter. At each time interval, [3H]thymidine incorporation was documented and found to be similar in the three groups. In conclusion, the results of this study indicate that total colectomy, and to a lesser extent abdominal surgery, induces the conversion of an intact, quiescent liver to a state of replicative competence. The results also suggest that, in addition to colectomy, the presence of mitogens and/or co-mitogens is required for further progression of hepatocytes through the cell cycle. Finally, a "primed" liver does not respond more promptly or vigorously to a regenerative stimulus than a "resting" liver.