Overexpression of cyclin E protein is closely related to the mutator phenotype of colorectal carcinoma.
OBJECTIVE
A subset of colorectal carcinomas are due to a deficiency in the DNA mismatch repair system. The molecular mechanisms of tumorigenesis in these tumors is not yet well understood. Deregulation of the cell cycle, specifically of the G(1) and S phases, is a hallmark of human cancers. Transition from the G(1) to the S phase is accelerated by increased cyclin E protein expression, and recent studies suggest that overexpression of cyclin E leads to chromosomal instability. The overexpression of cyclin E in a variety of human cancers, for example in colorectal, gastric, lung, breast, and kidney cancer, provides evidence that cyclin E plays a pivotal role in the cell cycle and replication. We examined whether the overexpression of cyclin E is related to the status of the mismatch repair system in colorectal carcinomas.


METHODS
Frozen tumor samples and adjacent normal colon mucosa obtained from 100 patients were subjected to microsatellite analysis, RT-PCR, western blot analysis and immunohistochemistry.


RESULTS
High microsatellite instability was detected in 13 tumors, and in 10 of these (77%) cyclin E protein was overexpressed at least twofold compared to normal mucosa. In contrast, only 28 of the remaining 87 microsatellite stable tumors (32%) overexpressed cyclin E. Lower molecular weight cyclin E proteins were present in 7 of 87 microsatellite stable carcinoma (8%), compared to 7 cases exhibiting lower molecular weight isoforms of 13 MSI carcinoma (54%).


CONCLUSIONS
Increased cyclin E protein expression and the appearance of lower molecular weight cyclin E proteins were significantly associated with MSI in colorectal tumors. The data indicate that increased and/or aberrant expression of cyclin E protein might contribute to the mutator phenotype of colorectal cancer.
D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis; D015870:Gene Expression; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats; D008970:Molecular Weight; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D019927:Cyclin E; D004273:DNA, Neoplasm; D005819:Genetic Markers; D020033:Protein Isoforms; D012333:RNA, Messenger