Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting Clusterin improves response to paclitaxel

Journal of Experimental & Clinical Cancer Research

Noriaki Sakuragi¹  Shinya Tanaka²  Lei Wang²  Masayoshi Hosaka¹  Takashi Mitamura¹  Yimin Han¹  Hidemichi Watari¹  Mohamed K Hassan³ 

[1] Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan;Laboratory of Cancer Research, Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan;Biotechnology Program, Zoology Dept., Faculty of Science, Port Said University, Port Said, 24151, Egypt

关键词: Chemo-resistance;    Ovarian Cancern;    Clusterinn;   

Others  :  827008
DOI  :  10.1186/1756-9966-30-113

 received in 2011-10-19, accepted in 2011-12-20,  发布年份 2011

【 摘 要 】

Background

Clusterin is a cytoprotective chaperone protein involved in numerous physiological processes, carcinogenesis, tumor growth and tissue remodelling. The purpose of this study was to investigate whether clusterin (CLU), an antiapoptotic molecule, could be a potential predictor molecule for ovarian cancer and whether or not targeting this molecule can improve survival of ovarian cancer patients.

Methods

Clusterin expression was compared between ten primary and their recurrent tumors from same patients immunohistochemically. We analyzed prognostic significance of CLU expression in another 47 ovarian cancer tissue samples by immunohistochemistry. We used small interference RNA to knock down CLU in the chemo-resistant ovarian cancer cell lines. KF-TX and SKOV-3-TX, paclitaxel-resistant ovarian cancer cells, were established from parental KF and SKOV-3 chemo-sensitive cell lines, respectively. Either siRNA or second generation antisense oligodeoxynucleotide against CLU (OGX-011), which is currently evaluated in clinical phase II trials in other cancer s, was used to modulate sensitivity to paclitaxel (TX) in ovarian cancer cells in vitro. Cellular viability assay, FACS analysis and annexin V staining were used to evaluate the comparative effect of CLU knocking down in ovarian cancer cells.

Results

Immunohistochemical analysis of CLU expression in primary ovarian cancer tissue specimens and their recurrent counterparts from same patients demonstrated higher expression of CLU in the recurrent resistant tumors compared with their primary tumors. High expression of CLU by immunohistochemistry among 47 surgical tissue specimens of early-stage (stage I/II) ovarian cancer, who underwent complete cytoreduction as a primary surgery, significantly related to poor survival, while none of other clinicopathological factors analyzed were related to survival in this patient cohort. Secretory CLU (s-CLU; 60 KDa) expression was upregulated in TX-resistant ovarian cancer cells compared to parental cells. Transfection of siRNA or OGX-011 clearly reduced CLU expression. Cell viability assay, FACS analysis and annexin V staining demonstrated that targeting CLU expression by siRNA or OGX-011 sensitized ovarian cancer cells to TX.

Conclusion

We conclude that CLU could be a potential molecular target to predict survival while targeting this s-CLU may improve survival of patients with ovarian cancer.

【 授权许可】

   
2011 Hassan et al; licensee BioMed Central Ltd.

【 图 表 】

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