Expression of cyclins and cdks throughout murine carcinogenesis.
The overexpression and/or amplification of cell cycle regulating genes is an important factor in the progression of cancer. Recent attention has been focused on several cyclin and cdks genes whose expression were increased in many types of tumor. In this study, we investigated the expression kinetics of cyclins A, B, D1, E and cdks 1, 2, 4, 6 by RT-PCR coupled with densitometry and correlated to the growth fraction (percentage of S cells). This analysis was performed using an experimental murine leukemic model, generated by in vivo administration of murine clonogenic cells Wehi-3b injected into balb-c mice. Differential expression of cyclins and cdks was observed between normal and tumoral cells with different patterns of expression between G1 and G2M cyclins-cdks. G1 cyclins cdks expression was significantly increased in tumor cells when compared to normal cells. In the same manner, G2M cyclins cdks expression was only observed in tumor cells at a lower level than for G1 cyclins cdks, but not detected in normal cells. These differences correlated with the growth fraction for both the G1 cyclins cdks (r = 0.91, 0.94, 0.85, 0.90 and 0.96 for cyclin D1, cyclin E, cdk2, cdk4 and cdk6, respectively) and the G2M cyclins cdks (r = 0.96, 0.97 and 0.93 for cyclins A, B and cdkl respectively). Analysis of cyclins cdks expression kinetics during tumoral progression shows that cyclins A, B and cdkl were expressed from the 12th day on of disease, increased until the death of the animals and correlated with the growth fraction (r = 0.94, 0.95 and 0.97 for cyclins A, B and cdk1 respectively) (n = 20). Overexpression of other cyclins cdks were observed, from the 6th day on for cyclin D1, the 12th day for cdk2 and cdk4, the 15th day for cdk6 and the 20th day for cyclin E. These increases persisted during tumoral progression and correlated with the growth fraction (r = 0.85, 0.94, 0.93, 0.96, and 0.98 for cyclin D1, cyclin E, cdk2, cdk4 and cdk6, respectively) (n = 20). Our results demonstrated that G1 and G2-M cyclins cdks mRNA levels were increased at approximately the same time of maximal tumor growth. Only cyclin D1 overexpression occured at the initiation of tumoral development, and could therefore be considered as an early marker of cell proliferation.
Yerly-Motta
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Cellular Immunology and Immunomolecular Therapeutic Laboratories, ETS Franche-Comté, Besançon, France. tim@besancon.net
Contassot
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E
Pavy
J J
JJ
Tiberghien
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P
Hervé
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P
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002455:Cell Division; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012334:RNA, Neoplasm / Q000032:analysis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D016213:Cyclins; D012334:RNA, Neoplasm; D018844:Cyclin-Dependent Kinases