n-Butyrate induces plasminogen activator inhibitor type 1 messenger RNA in cultured Hep G2 cells.

n-Butyrate, a short-chain aliphatic carboxylic acid with pleiotropic actions, is present at high concentrations in the portal circulation and thus may play an important role in the regulation of specific gene expression in the mammalian liver. We report here that n-butyrate can increase substantially the level of plasminogen activator inhibitor type 1 (PAI-1) messenger RNA (mRNA) in Hep G2 cells, up to eightfold above control cultures. Maximal effects occurred at a concentration of 3 mmol/L n-butyrate and with a treatment period of 8 to 12 hours. Increases in PAI-1 mRNA were accompanied by modest increases (twofold) in the encoded protein as assessed by specific enzyme-linked immunosorbent assay and by [35S]methionine incorporation into immunoprecipitable PAI-1 in the culture medium. Nuclear run-on studies showed that the rate of transcription of the PAI-1 gene did not appear altered by treatment with 3 mmol/L n-butyrate for 6 hours. The increases in steady-state PAI-1 mRNA caused by exposure to n-butyrate can be blocked by cycloheximide. Enhanced stability of mature PAI-1 transcript could not be demonstrated in Hep G2 cells treated with the carboxylic acid. We have reported previously that n-butyrate can reduce the level of beta-galactoside alpha 2,6-sialyltransferase expression in Hep G2 cells. That effect was attenuated with inhibitors of protein and RNA synthesis and was mediated at the post-transcriptional level. Thus, n-butyrate can influence the expression of multiple genes in this hepatoblastoma cell through its actions on events that appear to be posttranscriptional. These observations may be relevant to the normal physiology of the mammalian liver because of the high concentrations of n-butyrate and related compounds to which the organ is ordinarily exposed.

Determinants of differential liver-colonizing potential of variants of the MCA-38 murine colon cancer cell line.

We investigated factors that might contribute to the differing liver tumor colonizing potentials of MCA-38 colonic cancer cell line variants injected into the ileocolic veins of C57Bl/6J mice. Non-colonizing (MCA-38 CD) cells were sensitive to lysis by hepatic natural killer (NK) cells in vitro (51Cr-release assay) and cells with high liver-colonizing potential (MCA-38 LD) were resistant. Following abrogation of NK activity by treatment with anti-asialoGM1, liver-colonizing ability to LD cells but not CD cells was enhanced. MCA-38 CD cells were, however, capable of initial liver colonization after ileocolic vein injection. Differing patterns of membrane sialylation may have contributed to the contrasting hepatic tumorigenicities of LD and CD cells; beta-galactoside alpha 2,6-sialyltransferase mRNA levels and activity were approximately four-fold higher in LD than CD cells and qualitative and quantitative differences existed between their ganglioside profiles. In the MCA-38 model outlined, tumor cell susceptibility or resistance to NK lysis was a relatively unimportant determinant of liver-colonizing potential.