CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance

• Published in: The Prostate 2014-05, Vol.74 (6), p.602-617
• Main Authors: Ni, Jie, Cozzi, Paul J., Hao, Jing L., Beretov, Julia, Chang, Lei, Duan, Wei, Shigdar, Sarah, Delprado, Warick J., Graham, Peter H., Bucci, Joseph, Kearsley, John H., Li, Yong
• Format: Article
• Language: English
• Subjects: CD44 variant 6; Cell Line, Tumor; Cell Proliferation; chemoresistance; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Lymphatic Metastasis - genetics; Lymphatic Metastasis - pathology; Male; Phosphorylation; PI3K/Akt/mTOR pathway; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; radioresistance; Wnt pathway
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.22775

INTRODUCTION Prostate cancer (CaP) is the second leading malignancy in older men in Western countries. The role of CD44 variant 6 (CD44v6) in CaP progression and therapeutic resistance is still uncertain. Here, we investigated the roles of CD44v6 in CaP metastasis and chemo/radioresistance. Expression of CD44v6 in metastatic CaP cell lines, human primary CaP tissues and lymph node metastases was assessed using immunofluorescence and immunohistochemistry, respectively. METHODS Knock down (KD) of CD44v6 was performed in PC‐3M, DU145, and LNCaP cells using small interfering RNA (siRNA), and confirmed by confocal microscope, Western blot and quantitative real time polymerase chain reaction (qRT‐PCR). Cell growth was evaluated by proliferation and colony formation assays. The adhesive ability and invasive potential were assessed using a hyaluronic acid (HA) adhesion and a matrigel chamber assay, respectively. Tumorigenesis potential and chemo‐/radiosensitivity were measured by a sphere formation assay and a colony assay, respectively. RESULTS Over‐expression of CD44v6 was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of CD44v6 suppressed CaP proliferative, invasive and adhesive abilities, reduced sphere formation, enhanced chemo‐/radiosensitivity, and down‐regulated epithelial–mesenchymal transition (EMT), PI3K/Akt/mTOR, and Wnt/β‐catenin signaling pathway proteins in vitro. CONCLUSIONS Our findings demonstrate that CD44v6 is an important cancer stem cell‐like marker associated with CaP proliferation, invasion, adhesion, metastasis, chemo‐/radioresistance, and the induction of EMT as well as the activation PI3K/Akt/mTOR and Wnt signaling pathways, suggesting that CD44v6 is a novel therapeutic target to sensitize CaP cells to chemo/radiotherapy. Prostate 74:602–617, 2014. © 2014 Wiley Periodicals, Inc.