1. Modulation of different clusterin isoforms in human colon tumorigenesis
- Author
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Luigi Giusto Spagnoli, Flavia Pichiorri, Caterina Angeloni, Sabina Pucci, and Elena Bonanno
- Subjects
glycoprotein ,Cytoplasm ,Cancer Research ,Cell ,colon carcinoma ,medicine.disease_cause ,colon carcinogenesis ,Western blotting ,Cell membrane ,Extracellular matrix ,Clusterin/ApoJ ,protein glycosylation ,CLU protein ,chaperone ,Protein Isoforms ,cellular distribution ,nucleocytoplasmic transport ,biology ,Blotting ,apoptosis ,article ,colon tumor ,protein function ,Tumor progression ,Protein Transport ,medicine.anatomical_structure ,colon mucosa ,priority journal ,cancer grading ,immunohistochemistry ,Colonic Neoplasms ,isoprotein ,Neoplasm Invasiveness ,Blotting, Western ,Humans ,Clusterin ,Molecular Chaperones ,Glycoproteins ,Cell Nucleus ,cell cycle ,cancer invasion ,Western ,medicine.medical_specialty ,protein localization ,Settore MED/08 - Anatomia Patologica ,cancer growth ,Clusterin isoforms ,Internal medicine ,Genetics ,medicine ,metastasis ,controlled study ,human ,Cell adhesion ,protein expression ,Molecular Biology ,human cell ,human tissue ,clusterin ,CLU protein, human ,protein transport ,cell nucleus ,cytoplasm ,metabolism ,pathology ,physiology ,Endocrinology ,Settore MED/03 - Genetica Medica ,Progression marker ,biology.protein ,Cancer research ,Carcinogenesis ,Colon carcinoma - 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.
- Published
- 2004