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Competitive RNA-DNA Hybridization of Nuclear and Microsomal RNA during Diethylnitrosamine Hepatocarcinogenesis¹

Departments of Oncology and Pathology, McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

The livers of rats given diethylnitrosamine for 2 to 10 weeks when compared with normal untreated rats showed a qualitative loss of nuclear RNA species after 10 weeks of treatment that correlated with the first appearance of histologically identifiable primary hepatomas. Moreover, these species appeared related to those also missing from the nuclear RNA of the 5123C minimal-deviation hepatoma. No species of nuclear RNA unique to the carcinogentreated livers were detected. After 2, 4, and 10 weeks of injections, microsomal RNA from livers of diethylnitrosamine-treated rats showed an increase in species not usually present in the cytoplasm of normal liver. Between 4 and 10 weeks of diethylnitrosamine treatment, a marked qualitative loss of competitive efficiency of microsomal RNA with an apparent return to near-normal levels after 8 weeks of treatment was observed. RNA sequence changes in the cytoplasm are detected as early as 2 weeks after the start of the carcinogenic diet. This fact and the absence of any changes in RNA sequences detected in the nucleus after 10 weeks of feeding support the hypothesis that alteration of nuclear-to-cytoplasm transport of messenger RNA or stabilization of messenger RNA in the cytoplasm, rather than alteration in transcription, is the primary event in the initiation of the neoplastic transformation in liver.

¹ The work reported herein was supported in part by grants from the National Cancer Institute (CA-07175) and the American Cancer Society (E-588G). Portions of the work reported were taken from a thesis submitted by C. T. G. in partial fulfillment of the requirements for the Ph.D. degree at the University of Wisconsin.

² Postdoctoral trainee in Biochemical Pathology of the National Institute of General Medical Sciences (GM-00130). Present address: Armed Forcos Institute of Pathology, Washington, D. C. 20305.

³ Predoctoral trainee of the National Cancer Institute (TO1-CA-05002).

Received 6/ 1/72. Accepted 4/ 4/73.