Modulation of different clusterin isoforms in human colon tumorigenesis
- 2 February 2004
- journal article
- research article
- Published by Springer Nature in Oncogene
- Vol. 23 (13) , 2298-2304
- https://doi.org/10.1038/sj.onc.1207404
Abstract
Clusterin is a ubiquitous secretory heterodimeric disulfide-linked glycoprotein, which is implicated in several physiological processes, including immune regulation, cell adhesion and morphological transformation, lipid transportation, tissue remodelling, membrane recycling and cell–cell interactions. A large number of studies have focused their interest on clusterin gene products as mediators of cell cycle progression and cell death induction, although data on the different isoforms and their role in the different cell processes are still obscure. Recently, an increased clusterin expression in breast cancer has been reported. In order to elucidate the role of clusterin in tumor progression and whether one of its isoforms is preferentially expressed in tumorigenesis, we examined its presence throughout the different steps of human colon carcinoma, one of the best-characterized models of human tumor progression. The immunohistochemical observation of 30 bioptic and surgical colon specimens demonstrated a cell compartment clusterin translocation from the nucleus to the cytoplasm directly related to tumor progression. In fact, a nuclear localization found in healthy colonic mucosa is consistent with the involvement of the proapoptotic nuclear form in the regulation of cell cycle progression and in cell death induction. The progression towards high-grade and metastatic carcinoma leads to cytoplasmic clusterin distribution. Protein extracts from freshly isolated cells of the same patients confirm in high-grade carcinomas with metastatic nodes the complete loss of the proapoptotic nuclear form and a cytoplasmic overexpression of the highly glycosylated form. Data obtained from in vitro experiments confirm that this form is released in the extracellular space and corresponded to the fully glycosylated one. These data suggest that the controversial data on clusterin function in tumors may be related to the pattern shift of its isoform production. As the secreted form of clusterin is correlated to cell matrix formation, cell membrane remodeling and cell–cell adhesion, the overexpression of this form in highly aggressive tumors and metastatic nodes could be a potential new prognostic and predictive marker for colon carcinoma aggressiveness.Keywords
This publication has 23 references indexed in Scilit:
- Alterations in the post-translational modification and intracellular trafficking of clusterin in MCF-7 cells during apoptosisCell Death & Differentiation, 2003
- Synthesis and Functional Analyses of Nuclear Clusterin, a Cell Death ProteinJournal of Biological Chemistry, 2003
- Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progressionOncogene, 2002
- Tumor specific modulation of KU70/80 DNA binding activity in breast and bladder human tumor biopsiesOncogene, 2001
- Overexpression of Clusterin in Human Breast CarcinomaThe American Journal of Pathology, 2000
- Lack of Association between Enhanced TRPM-2/Clusterin Expression and Increased Apoptotic Activity in Sex-Hormone-Induced Prostatic Dysplasia of the Noble RatThe American Journal of Pathology, 1998
- Role of clusterin in cell adhesion during early phases of programmed cell death in P19 embryonic carcinoma cellsBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1996
- Interaction of Transforming Growth Factor β Receptors with Apolipoprotein J/ClusterinBiochemistry, 1996
- Distinct sites of production and deposition of the putative cell death marker clusterin in the human thymus.Journal of Clinical Investigation, 1992
- SP-40,40, a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis.Journal of Clinical Investigation, 1988