Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer

Abstract

Clusterin (CLU) is a multivalent glycoprotein with ubiquitous tissue distribution. To address the possible differential functional roles assumed by different isoforms of CLU in the progression of human ovarian cancer, we constructed 2 human ovarian cancer cell models that represent examples of contradistinctive CLU expression levels. One is constitutively overexpressing different clusterin isoforms in SKOV3 cells by transfection of the 3 different expression vectors, another is silencing the intrinsically expressing clusterin in cisplatin-resistant human A2780-cis(CP70) tumor cells with the usage of shRNA-mediated CLU gene silencing. Then, the different cellular localization, biological effects, and functional roles played in tumor progression and drug resistances were studied. We found that (i) in the distinct cellular contexts of human ovarian carcinoma SKOV3 and CP70 cells assayed, sCLU is a central molecule in cell homeostasis that functions as a cytoprotective protein, whereas nCLU is proapoptotic; (ii) In SKOV3 cells, nuclear localization of the truncated CLU is NLS dependent, without which the pnCLU protein was sequestrated in cytoplasm to prevent cytotoxicity. (iii) sCLU plays a significant role in the development of the chemoresistance phenotype in ovarian cancer cells. Moreover, with the CLU-specific shRNA oligonucleotides, we successfully sensitized cells for chemotherapy, and inhibited cells' proliferation, migration and invasion. Collectively, our results reveal that, CLU gene expression might play a crucial role in ovarian cancer progression, adaptation and eventual resistance to chemotherapy through differential processing of CLU isoforms. Specifically, sCLU as an antiapoptotic protein, upregulated in an adaptive cell-survival manner by chemotherapy, confers resistance to various cell-death triggers. ' UICCKey words: clusterin; ovarian carcinoma; RNAi; chemoresistance; metastasis Ovarian cancer, the leading cause of death from gynecological malignancy, is the seventh most common malignancy in women worldwide and is the fourth leading cause of death from malignant disease among American women. In more than two thirds of the cases, patients show widespread metastatic dissemination at time of the initial presentation. 1 Because of advances in surgical management and chemotherapeutic options over the last 3 decades, the median survival rate for ovarian cancer patients has improved. Nevertheless, overall survival has not significantly changed. Cisplatin-based combination chemotherapy is initially an effective mechanism to arrest malignancy. However, after preliminary success in tumor regression, recurrence and resistance to further chemotherapeutic treatment often ensues. This amplification in drug resistance has also been correlated with the development of a broad cross-resistance in ovarian cancer to other unrelated chemotherapeutic compounds. 2 Therefore, shortages of suitable biologic markers, and limitations in the timely screening methods, early metastasis and resistance to anticancer chemother...

Identification of novel epithelial ovarian cancer biomarkers by cross-laboratory microarray analysis

“…In the top 10 up-regulated DEGs (abnormal vs normal), EPCAM, CLU, HLA-DRB1, HLA-DRA, MSLN and CD74 had been reported to be associated with ovarian cancer. In these genes, overexpression of EPCAM was associated with primary, metastatic, and recurrent/chemotherapy-resistant epithelial ovarian cancer [15] ; High clustering (CLU) gene expression was associated with disease progression, chemoresistance and metastasis of ovarian cancer [16] . Binding of membrane-bound mesothelin (MSLN) to ovarian cancer antigen CA125 mediated heterotypic cell adhesion [17] .…”

Tcf21 regulates the specification and maturation of proepicardial cells

“…Compellingly, these genes have previously been ascribed roles in modulating ECM remodeling, cell adhesion, migration and epithelial-mesenchymal interactions, and frequently in the context of human malignancies and diseases, including Alzheimer's, Noonan syndrome and cardiovascular disorders (Jones and Jomary, 2002;Ny et al, 2002;Lin et al, 2005;Plaisier et al, 2005;Lin et al, 2006;Hu et al, 2007;Wei et al, 2009;Lee et al, 2010;Mehta and Parker, 2010;Fan et al, 2011;Tsai et al, 2011). Furthermore, with current data showing that differential transcriptional competency within the PEO can give rise to various EPDC populations (Mikawa and Gourdie, 1996;Männer, 1999;Jenkins et al, 2005;Guadix et al, 2006;Smith et al, 2011;Acharya et al, 2012;Katz et al, 2012) and recent findings that adult resident cardiac stem cells have a PEO origin (Chong et al, 2011), further investigation into the function of these genes during epicardium formation might provide a better understanding of their roles during normal cardiac development and human disease.…”

Towards an Animal Model of Ovarian Cancer: Cataloging Chicken Blood Proteins Using Combinatorial Peptide Ligand Libraries Coupled with Shotgun Proteomic Analysis for Translational Research

“…Moreover, clusterin has been identified from chicken serum and plasma samples. Elevated expression of clusterin was found in primary ovarian tumor tissues (Hassan et al, 2011, Yang et al, 2012 and paclitaxel-resistant ovarian cancer cells (Hassan et al, 2011) and was correlated with impaired prognostic outcome (Wei et al, 2009, Yang et al, 2009. Apart from those high-and medium-abundance proteins, several low-abundance potential biomarkers were also found in our list.…”