A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate
A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate
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DOI：
10.1016/j.ijrobp.2013.10.019
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发表时间：
2014-01-01
影响因子：
7
通讯作者：
Kim, Hyeong-Reh Choi
中科院分区：
文献类型：
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作者：
Christensen, Michael;Najy, Abdo J.;Kim, Hyeong-Reh Choi
目的：磷酸和紧张素同源基因(PTEN)缺失或突变是前列腺癌(PCa)常见的基因异常，可诱导血小板衍生生长因子D(PDGF D)信号转导。方法与材料：以PTEN野生型(PTEN+/+)和PTEN基因敲除(PTEN-/-)的小鼠前列腺上皮细胞系为研究对象，研究PTEN/PDGF轴在放射反应中的作用。用小发夹RNA(ShRNA)慢病毒载体转导PTEN-/-细胞，该慢病毒载体含有打乱的核苷酸(SCRM)或针对PDGFD的序列(ShPDGFD)。通过皮下注射雄性裸鼠和体外Matrigel三维(3D)培养评价这些细胞系的成瘤性和形态发生。根据PTEN状态和PDGFD的表达水平，检测照射对克隆存活、细胞迁移和侵袭的影响。结果：PTEN-/-细胞在动物体内具有高度的致瘤性，并在3D培养中有效地形成了肿瘤灶。重要的是，这些细胞系中PDGFD的缺失显著减少了这些表型。此外，与PTEN-/-相比，PTEN-/-细胞在体外表现出更高的克隆存活率，而PDGFD的减弱显著逆转了这种辐射抵抗表型。PTEN-/-细胞在基线和照射后表现出更大的迁移和侵袭潜力。PTEN-/-细胞的基本和辐射诱导的迁移和侵袭表型都需要PDGFD的表达。有趣的是，这些差异与细胞凋亡和细胞周期重新分配无关，因为它们没有明显的差异。结论：我们认为在PTEN功能缺失的情况下，PDGF D是一个潜在的抗PCa治疗的靶点，值得进一步的实验室评估和临床研究。(C)2014年爱思唯尔公司。
Purpose: Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model.Methods and Materials: PTEN wild-type (PTEN+/+) and PTEN knockout (PTEN-/-) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGFD expression levels. PTEN-/- cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGFD (shPDGFD). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen.Results: PTEN-/- cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGFD in these cell lines drastically diminished these phenotypes. Furthermore, PTEN-/- cells demonstrated increased clonogenic survival in vitro compared to PTEN-/-, and attenuation of PDGFD significantly reversed this radioresistant phenotype. PTEN-/- cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN-/- cells required PDGFD expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference.Conclusions: We propose that PDGF D represents a potentially promising target for PCa treatment resistance in the absence of PTEN function, and warrants further laboratory evaluation and clinical study. (C) 2014 Elsevier Inc.