Possible involvement of c‐myc but not ras genes in hepatocellular carcinomas developing after spontaneous hepatitis in LEC rats

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Abstract
LEC (Long‐Evans with a cinnamon‐like coat color) rats develop hepatocellular carcinomas (HCCs) spontaneously. We examined mutations of codons 12, 13, and 61 of the Ha‐ras, Ki‐ras, and N‐ras genes in four HCCs by the polymerase chain reaction (PCR)‐single‐stranded DNA direct sequencing method. No ras gene mutations were observed, suggesting that ras activation is not involved in spontaneous hepatocarcinogenesis in LEC rats. The expression of mRNAs for c‐myc, Ha‐ras, c‐raf, and the protein phosphatase 2Aα gene (PP‐2Aα) was also examined in the four HCCs by northern blot analysis. Three of the four HCCs had c‐myc expression levels approximately 30‐fold higher than that in the liver of control Long‐Evans rats with an agouti coat color (LEA), a sibling line of LEC rats, while the remaining HCC had an expression level sevenfold higher than that of control. In contrast, the expression levels of the Ha‐ras, c‐raf, and PP‐2Aα genes were the same as those in the livers of control rats. Studies of c‐myc expression and mitotic index in five other HCCs, two hyperplastic nodules, and two nontumorous portions of livers of HCC‐bearing LEC rats that had chronic‐phase hepatitis suggested that the high level of c‐myc gene expression was not due only to increased cell proliferation but might possibly be more integrally involved in hepatocarcinogenesis.

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