PTEN Regulates PDGF Ligand Switch for β-PDGFR Signaling in Prostate Cancer
PTEN Regulates PDGF Ligand Switch for β-PDGFR Signaling in Prostate Cancer
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DOI：
10.1016/j.ajpath.2011.11.021
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发表时间：
2012-03-01
影响因子：
6
通讯作者：
Kim, Hyeong-Reh Choi
中科院分区：
文献类型：
--
作者：
Conley-LaComb, M. Katie;Huang, Wei;Kim, Hyeong-Reh Choi
血小板衍生生长因子（PDGF）家族成员是调节细胞增殖、迁移和转化的有效生长因子。临床研究表明，PDGF受体β (β -PDGF)及其配体PDGF D在原发性前列腺癌和骨转移中均上调，而PDGF B作为β - pdgfr的经典配体，在临床样本中并不常见。在这项研究中，我们研究了肿瘤抑制磷酸酶和。在前列腺特异性、条件PTEN敲除小鼠模型和由这些小鼠建立的小鼠前列腺上皮细胞系中，10号染色体上的tensin同源物缺失（PTEN）在调节PDGF表达水平中的作用。我们发现PDGF D和β - pdgfr表达水平在pten缺失的肿瘤细胞中增加，同时PDGF B表达降低。在Akt异构体中，小鼠PTEN-null细胞中Akt3表达的增加最为显著，磷脂酰肌醇3-激酶/Akt活性对于维持PDGF - D和β - pdgfr表达的增加至关重要。在体外缺失PTEN导致正常小鼠前列腺上皮细胞PDGF配体从PDGF B向PDGF D转换，进一步证明PTEN调节这种配体转换。在人类前列腺癌细胞系中，PTEN状态和PDGF亚型之间也存在类似的关联。综上所述，这些结果提示PTEN缺失可能通过PDGF - D/ β - pdgfr信号转导促进前列腺癌进展的机制。（中国病理杂志，2012,180:1017-1027 DOI: 10.1016/ j.j ajpath.2011.11.021）
Platelet-derived growth factor (PDGF) family members are potent growth factors that regulate cell proliferation, migration, and transformation. Clinical studies have shown that both PDGF receptor beta (beta-PDGF) and its ligand PDGF D are up-regulated in primary prostate cancers and bone metastases, whereas PDGF B, a classic ligand for beta-PDGFR, is not frequently detected in clinical samples. In this study, we examined the role of the tumor suppressor phosphatase and. tensin homologue deleted on chromosome 10 (PTEN) in the regulation of PDGF expression levels using both a prostate-specific, conditional PTEN-knockout mouse model and mouse prostate epithelial cell lines established from these mice. We found an increase in PDGF D and beta-PDGFR expression levels in PTEN-null tumor cells, accompanied by a decrease in PDGF B expression. Among Akt isofarms, increased Akt3 expression was most prominent in mouse PTEN-null cells, and phosphatidylinositol 3-kinase/Akt activity was essential for the maintenance of increased PDGF D and beta-PDGFR expression. In vitro deletion of PTEN resulted in a PDGF ligand switch from PDGF B to PDGF D in normal mouse prostate epithelial cells, further demonstrating that PTEN regulates this ligand switch. Similar associations between PTEN status and PDGF isoforms were noted in human prostate cancer cell lines. Taken together, these results suggest a mechanism by which loss of PTEN may promote prostate cancer progression via PDGF D/beta-PDGFR signal transduction. (Am J Pathol 2012, 180:1017-1027 DOI: 10.1016/j.ajpath.2011.11.021)