Expression of c-Ki-ras, c-Ha-ras, and c-myc in specific cell types during hepatocarcinogenesis.

Abstract

We examined the expression of six proto-oncogenes in (i) whole rat liver and isolated liver cell populations during the course of hepatocarcinogenesis induced by a choline-deficient diet containing 0.1% ethionine and (ii) fetal rat liver at different stages of development. The abundance of c-Ki-ras, c-Ha-ras, and c-myc transcripts in polysomal polyadenylated RNA from liver cells increased by 2 weeks after the start of the carcinogenic diet. c-Ki-ras and c-myc expression remained elevated during the 35 weeks of the diet, whereas c-Ha-ras transcripts increased transiently. A primary tumor sampled at 35 weeks after the carcinogenic diet was started contained high levels of both c-Ki-ras and c-myc RNA. The abundance of c-src transcripts was unchanged throughout carcinogenesis; c-abl and c-mos transcripts were not detected in either preneoplastic or neoplastic livers. To determine which cell types within the liver contained proto-oncogene transcripts, we isolated hepatocytes, oval cells, and bile duct cells from normal and preneoplastic livers. The results indicate that proto-oncogenes are expressed differentially in these cell types during hepatocarcinogenesis and that the expression of c-Ki-ras and c-myc is high in oval cells throughout carcinogenesis. In developing livers, c-Ki-ras, c-Ha-ras, and c-myc transcript levels were high at 17 days of gestation but reached the low values characteristic of adult rat livers between 20 days of gestation and 3 days after birth.

Developmentally-regulated expression of murine K-ras isoforms

“…Quantitative analysis of H-and K-ras expression during ontogeny revealed constant mRNA abundance (MuÈ ller et al, 1982), except for a fall in K-ras in late gestation (MuÈ ller, 1983;MuÈ ller et al, 1983). Highest levels of K-ras were expressed in developing rat liver around E17 (Yaswen et al, 1985). These ®ndings may be compared with the stage-speci®c induction of other c-onc genes such as erbA, src (E9), myc (E13) (Slamon and Cline, 1984) and abl (E9), or the suppression of fos at E9 (MuÈ ller et al, 1982).…”

“…Our studies of the same cells ( SW480, Calu-1, SK-N-SH, T24, peripheral blood lymphocytes) are broadly in agreement (DJW et al, unpublished data). Subsequent reports have used a restricted range of probes which would not distinguish the K-ras isoforms: HiHi 3 (Campisi et al, 1984;Ellis et al, 1981;Lockett and Sleigh, 1987;Sejersen et al, 1985), HiHi 380 (Ellis et al, 1981(Ellis et al, , 1982Goyette et al, 1984;Yaswen et al, 1985) and pY413 (George et al, 1985;Leon et al, 1987). Where PCR has been used, primers were chosen within exons 1 and 3 (Pal et al, 1993).…”

Transforming Growth Factor-α Inhibits the Intrinsic Pathway of c-Myc-Induced Apoptosis through Activation of Nuclear Factor-κB in Murine Hepatocellular Carcinomas

“…Deregulation of c-Myc gene expression due to amplification or gene rearrangement is frequently observed in experimentally derived hepatocellular carcinomas (16)(17)(18) as well as in primary liver tumors (19,20). Furthermore, ectopic expression of c-Myc in murine hepatocytes promotes liver neoplastic development (21), and targeted inactivation of c-Myc induces tumor regression of c-Myc-induced hepatocellular carcinomas (22).…”

Bystin-like protein is upregulated in hepatocellular carcinoma and required for nucleologenesis in cancer cell proliferation

“…c-myc, whose expression tightly correlates with the proliferative potential of the cell, is a key transforming agent in the etiology of human cancer [21,22]. Amplification and overexpression of c-myc have been found in both chemical hepatocarcinogenesis in rat [23][24][25] and in human HCC cells [26][27][28]. Taken together, these data raise the possibility that BYSL may play important roles in rapid cell growth and proliferation seen in HCC.…”