Tumor-specific hyperactive low-molecular-weight cyclin E isoforms detection and characterization in non-metastatic colorectal tumors.
OBJECTIVE
Several molecules involved in cancer biology have been studied as potential prognostic markers. Recently, overexpression of cyclin E and its low-molecular-weight (LMW) isoforms has been reported to be the most prominent prognostic marker in breast cancer, surpassing proliferation index, ploidy, and axillary nodal involvement. Furthermore, cyclin E and p53 are considered the main factors controlling the euploid equilibrium in human cells. We investigated the status of cyclin E and p53 in cell lines and tissue samples of colorectal cancer, one of the leading causes of death from a tumor in the Western world.


METHODS
We analyzed colorectal cancer cells, from established cell lines and patient specimens, to determine the protein levels of cyclin E and p53, and to detect p53 and APC mutations, microsatellite and chromosome instability. In addition, we assessed the presence of cyclin E LMW isoforms and their enzymatic activity.


RESULTS
Colorectal cancer cells expressed hyperactive LMW forms both in vitro and in vivo. These tumor-specific isoforms are correlated to genomic instability even in p53-proficient cells, and represented a constant feature in the tumors analyzed.


CONCLUSIONS
In colorectal cancer, the formation of cyclin E LMW forms is an early event leading to DNA-damage checkpoint-independent proliferation. Collectively, our results provide evidence that evaluation of LMW forms could represent a novel tool in the molecular characterization of colorectal tumors aimed at identifying sensitive prognostic factors and uncovering subsets of high-risk patients within the traditional categories.
Corin
Irina
I
Department of Oncology, Sahlgrenska Hospital, Gothenburg University, Gothenburg, Sweden.
Di Giacomo
Marilena C
MC
Lastella
Patrizia
P
Bagnulo
Rosanna
R
Guanti
Ginevra
G
Simone
Cristiano
C
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000175:diagnosis*; D019927:Cyclin E / Q000032:analysis*; D004249:DNA Damage; D004252:DNA Mutational Analysis; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008970:Molecular Weight; D011379:Prognosis; D020033:Protein Isoforms / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; D019927:Cyclin E; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53