CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance
CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance
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DOI：
10.1002/pros.22775
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发表时间：
2014-05-01
期刊：
影响因子：
2.8
通讯作者：
Li, Yong
中科院分区：
文献类型：
--
作者：
Ni, Jie;Cozzi, Paul J.;Li, Yong
前言前列腺癌（CaP）是西方国家老年男性的第二大恶性肿瘤。CD 44变体6（CD 44 v6）在CaP进展和治疗耐药性中的作用仍不确定。在此，我们研究了CD 44 v6在CaP转移和化疗/放射抵抗中的作用。分别用免疫荧光和免疫组织化学方法检测转移性CaP细胞系、人原发性CaP组织和淋巴结转移瘤中CD 44 v6的表达。方法应用小分子干扰RNA（siRNA）对PC-3 M、DU 145和LNCaP细胞中的CD 44 v6进行敲低（KD），并通过共聚焦显微镜、Western blot和定量真实的时间聚合酶链反应（qRT-PCR）进行验证。通过增殖和集落形成试验评价细胞生长。分别采用透明质酸（HA）粘附试验和基质胶小室试验评估粘附能力和侵袭潜力。肿瘤发生潜力和化疗/放射敏感性分别通过球体形成试验和集落试验测定。结果CD 44 v6在原发性CaP组织和淋巴结转移癌组织中均呈高表达，包括癌细胞和癌旁间质细胞。CD 44 v6 KD抑制CaP增殖、侵袭和粘附能力，减少球体形成，增强化疗/放射敏感性，并下调上皮-间质转化（EMT）、PI 3 K/Akt/mTOR和Wnt/β-catenin信号通路蛋白。结论CD 44 v6是一种重要的肿瘤干细胞样标志物，与CaP细胞增殖、侵袭、粘附、转移、放化疗耐药、EMT诱导以及PI 3 K/Akt/mTOR和Wnt信号通路的激活有关，提示CD 44 v6是一种新的治疗靶点，可使CaP细胞对放化疗敏感。前列腺74：602-617，2014年。(c)2014年威利期刊公司
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/beta-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. (c) 2014 Wiley Periodicals, Inc.