Differential tumorigenic potential and matriptase activation between PDGF B versus PDGF D in prostate cancer.
Differential tumorigenic potential and matriptase activation between PDGF B versus PDGF D in prostate cancer.
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DOI：
10.1158/1541-7786.mcr-12-0071
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Kim HR
中科院分区：
文献类型：
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作者：
Najy AJ;Won JJ;Movilla LS;Kim HR
血小板源性生长因子（PDGF A、B、C和D）及其受体（α-PDGFR和β-PDGFR）在生理和病理条件（包括肿瘤发生）中起着不可或缺的作用。转化性β-PDGFR在前列腺癌进展过程中过表达和激活，但其互补配体的鉴定和功能意义尚未阐明。本研究使用过表达β-PDGFR配体PDGF B和PDGF D的非恶性前列腺上皮细胞检测了这些配体的潜在致癌功能。在我们的模型中，PDGF D在体外比PDGF B更有效地诱导细胞迁移和侵袭。重要的是，PDGF D支持体内前列腺上皮细胞肿瘤发生，并且与PDGF B相比显示出增加的肿瘤血管生成。对丝裂原活化蛋白激酶和磷酸肌醇3-激酶途径的自分泌信号分析发现，PDGF D特异性激活c-jun-NH 2-激酶（JNK）信号级联。使用短发夹RNA和药物抑制剂，我们表明PDGFD介导的表型转化是β-PDGFR和JNK依赖性的。重要的是，我们在前列腺上皮细胞中发现了PDGF D特异性增加丝氨酸蛋白酶matriptase的脱落和激活的新发现。据我们所知，我们的研究首次显示了配体特异性β-PDGFR信号传导以及基质蛋白酶活性的PDGF D特异性调节及其通过脱落的空间分布。结合我们先前的发现，即间质蛋白酶是PDGF D的蛋白水解激活剂，本研究提供了对癌症进展期间蛋白水解网络和PDGF信号环的信号放大的分子见解。
The platelet-derived growth factors (PDGF A, B, C, and D) and their receptors (α-PDGFR and β-PDGFR) play an indispensible role in physiologic and pathologic conditions, including tumorigenesis. The transformative β-PDGFR is overexpressed and activated during prostate cancer progression, but the identification and functional significance of its complementary ligand have not been elucidated. This study examined potential oncogenic functions of β-PDGFR ligands PDGF B and PDGF D, using nonmalignant prostate epithelial cells engineered to overexpress these ligands. In our models, PDGF D induced cell migration and invasion more effectively than PDGF B in vitro. Importantly, PDGF D supported prostate epithelial cell tumorigenesis in vivo and showed increased tumor angiogenesis compared with PDGF B. Autocrine signaling analysis of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways found PDGF D–specific activation of the c-jun-NH2-kinase (JNK) signaling cascade. Using short hairpin RNA and pharmacologic inhibitors, we showed that PDGFD-mediated phenotypic transformation is β-PDGFR and JNK dependent. Importantly, we made a novel finding of PDGF D–specific increase in the shedding and activation of the serine protease matriptase in prostate epithelial cells. Our study, for the first time to our knowledge, showed ligand-specific β-PDGFR signaling as well as PDGF D–specific regulation of matriptase activity and its spatial distribution through shedding. Taken together with our previous finding that matriptase is a proteolytic activator of PDGF D, this study provides a molecular insight into signal amplification of the proteolytic network and PDGF signaling loop during cancer progression.