Abstract
Abstract Aim: The role of CD44 variant 6 (CD44v6) in prostate cancer (CaP) metastasis and progression remains unclear. The aim of this study was 1) to examine the expression of CD44v6 in metastatic CaP cell lines, and normal, benign hyperplastic, and CaP tissues in different stages and lymph node metastases; 2) to investigate the role of CD44v6 in CaP progression, metastasis and therapy resistance as well as underlying pathways in vitro for a potential therapeutic target. Methods: Immunohistochemical/immunocytochemical analysis using an anti-CD44V6 monoclonal antibody (MAb) was performed on metastatic CaP cell lines and paraffin embedded specimens from patients (n=10) who underwent radical prostatectomy (RP), lymph node metastases (n=10), benign prostatic hyperplasia (BPH) (n=10), and normal prostate tissues (n=10). The immunostaining results from CaP cell lines were further confirmed by Western blot. The functional roles of CD44v6 in CaP metastasis and chemo- and radio-sensitivity were examined by knocking down (KD) CD44v6 gene using siRNAs in PC-3M, DU145 and LNCaP CaP cells, respectively and then performing cell invasion, colony formation, proliferation rate, sphere formation, chemo- and radio-sensitivity assays. Results: The expression of CD44v6 was found moderately to strongly positive in androgen-responsive (LNCaP, LNCaP-LN3) and androgen-nonresponsive (PC-3, PC-3M, DU145 and LNCaP-C4B2) metastatic CaP cell lines. The expression of CD44v6 was found negative in normal prostate and BPH tissues, and moderately to strongly positive primary CaP tissues and lymph node metastases. Three CD44v6-KD cell lines showed notable decreases in functions of invasion, colony formation, proliferation, sphere formation, and an increase in chemodrug and radiation sensitivity, compared to the parental cell lines, respectively. Obvious down-regulation of PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways were observed in three CD44v6-KD cell lines by Western Blot. Conclusions: CD44v6 is a biomarker involved in CaP progression and metastasis, associated with CaP chemo-/radio-resistance via PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways and could be an ideal potential therapeutic target for the treatment of castrate-resistant prostate cancer (CRPC). The in vivo study of CD44v6 functions in CaP animal models is ongoing in our laboratory. Citation Format: Jie Ni, Paul Cozzi, Jingli Hao, Julia Beretov, Lei Chang, Wei Duan, Warick Delprado, Peter Graham, Joseph Bucci, John Kearsley, Yong Li. CD44 isoform variant 6 is associated with prostate cancer progression, metastasis and chemo-/radio-resistance via PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4005. doi:10.1158/1538-7445.AM2014-4005
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