Clusterin Expression in the Early Process of Pancreas Regeneration in the Pancreatectomized Rat

Department of Pharmacology and BK21 Program for Medical Sciences, College of Medicine, Korea University, Seoul, Korea.
Journal of Histochemistry and Cytochemistry (Impact Factor: 1.96). 11/2003; 51(10):1355-65. DOI: 10.1177/002215540305101012
Source: PubMed


We have previously reported upregulation of clusterin at the time of islet cell regeneration after beta-cell injury. This led us to speculate that clusterin might be involved in the neogenic regeneration of the pancreas. Clusterin expression was examined throughout the process of pancreatic neogenesis in pancreatectomized rats. For in vitro analysis, duct cells were isolated from the rat pancreas and clusterin cDNA was transfected for its overexpression. Clusterin and its mRNA increased significantly in the early phase of regeneration, particularly at 1-3 days after pancreatectomy. Clusterin was transiently expressed in the differentiating acinar cells but faded afterwards. Interestingly, these clusterin cells were negative for PCNA (proliferating cell nuclear antigen), whereas most epithelial cells in ductules in the regenerating tissue showed extensive proliferative activity. Clusterin expression was also detected in some endocrine cells of the regenerating tissue. Transfection of clusterin cDNA into primary cultured duct cells resulted in a 2.5-fold increase in cell proliferation and induced transformation of non-differentiated duct cells into differentiated cells displaying cytokeratin immunoreactivity. Taken together, these results suggest that clusterin may play essential roles in the neogenic regeneration of pancreatic tissue by stimulating proliferation and differentiation of duct cells.

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    • "Transfection of clusterin cDNA into primary cultured pancreatic duct cells resulted in a 2.5-fold increase in cell proliferation and induced transformation of nondifferentiated duct cells into differentiated cells displaying cytokeratin immunoreactivity. These results confirm that CLU may play essential roles in the neogenic regeneration of pancreatic tissue by stimulating proliferation and differentiation of duct cells.57 "
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    ABSTRACT: Clusterin is a heterodimeric disulfide-linked glycoprotein (449 amino acids) isolated in the rat prostate after castration. It is widely distributed in different tissues and highly conserved in species. There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others. Its overexpression should be considered as a nonspecific cellular response to a wide variety of tissue insults like cytotoxic chemotherapy, radiation, excess of free oxygen radicals, androgen or estrogen deprivation, etc. A review of the recent literature strongly suggests potential roles for custirsen in particular, and proapoptosis treatments in general, as novel modalities in cancer management. Inhibition of clusterin is known to increase the cytotoxic effects of chemotherapeutic agents, and custirsen, a second-generation antisense oligonucleotide that blocks clusterin, is being tested in a Phase III clinical trial after successful results were achieved in Phase II studies. A major issue in cancer evolution that remains unanswered is whether clusterin represents a driving force of tumorigenesis or a late phenomenon after chemotherapy. This review presents preclinical data that encourages trials in various types of cancer other than advanced castration-resistance prostate cancer and discusses briefly the appropriate timing for clusterin inhibition in the clinical context.
    OncoTargets and Therapy 03/2014; 7:447-456. DOI:10.2147/OTT.S58622 · 2.31 Impact Factor
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    • "Imunohistochemical staining was performed as described previously [7]. All surgical specimens were fixed in 10% formalin, embedded in paraffin, and consecutively sectioned at 5 μm. "
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    ABSTRACT: Clusterin is known to be expressed in many human neoplasms, and is believed to participate in the regeneration, migration, and anti-apoptosis of tumor cells. However, few reports have addressed the relationship between the manifestation of clusterin and clinicopathologic parameters in pancreas cancer patients. In the present study, the authors investigated the expression of clusterin and its clinical significance in pancreatic adenocarcinoma. Immunohistochemical staining was performed for clusterin in tumor tissues obtained from patients who received pancreatic resection with radical intent, and the associations of clusterin expression with various clinicopathologic parameters were analyzed in addition to the relation between its expression and survival. Immunoreactivity for clusterin was observed in 17 of the 52 (33%) pancreatic adenocarcinomas examined. In addition, clusterin positivity was found to be associated with preoperative serum carcinoembryonic antigen level, perineural invasion, and, most strongly, lymph node metastasis. The survival analysis identified tumor differentiation and lymph node metastasis as the only significant prognostic factors. Although not an independent prognostic factor, clusterin immunoreactivity can be used in conjunction with lymph node metastasis to predict survival in cases of pancreatic adenocarcinoma.
    World Journal of Surgical Oncology 07/2012; 10(1):146. DOI:10.1186/1477-7819-10-146 · 1.41 Impact Factor
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    • "We also have shown that transfectionmediated expression of clusterin significantly increases the replication of MIN6 cells and improves the differentiation of beta-cells from rat duct cells (Kim et al., 2006). Moreover, clusterin is specifically expressed in the early process of pancreas regeneration in both developing exocrine and endocrine cells, suggesting a potential role in pancreatic regeneration (Min et al., 2003). These results led us to evaluate endocrine and exocrine pancreas regeneration in clusterin knock-out mice (CLU "
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    ABSTRACT: Based on our previous observations that clusterin induction accompanies pancreas regeneration in the rat, we sought to determine if regeneration might be impaired in mice that lacked clusterin. We studied the impact of absent clusterin on morphogenic and functional features of regenerating pancreas. Clusterin induction was accompanied in the regenerating pancreas by a robust development of new lobules with ductules, acini, and endocrine islets in wild type after partial pancreatectomy. In clusterin knock-out mice, however, pancreatectomy resulted in a poor formation of regenerating lobule. In particular, regeneration of beta-cells was also significantly reduced and was associated with persistent hyperglycemia. Duct cells obtained from pancreatectomized clusterin knock-out mice exhibited impaired beta-cell formation in vitro; this was restored by administration of exogenous clusterin. We suggest that clusterin plays a critical role to promote both exocrine and endocrine regeneration following pancreas injury, as well as for in vitro beta-cell regeneration.
    Developmental Dynamics 03/2011; 240(3):605-15. DOI:10.1002/dvdy.22556 · 2.38 Impact Factor
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