Stromal hyaluronan interaction with epithelial CD44 variants promotes prostate cancer invasiveness by augmenting expression and function of hepatocyte growth factor and androgen receptor.
Stromal hyaluronan interaction with epithelial CD44 variants promotes prostate cancer invasiveness by augmenting expression and function of hepatocyte growth factor and androgen receptor.
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DOI：
10.1074/jbc.m110.104273
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发表时间：
2010-06-25
期刊：
影响因子：
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通讯作者：
Misra S
中科院分区：
文献类型：
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作者：
Ghatak S;Hascall VC;Markwald RR;Misra S
我们研究的主要目的是确定间质微环境在前列腺癌恶性行为中的意义。基质源性生长因子/细胞因子和透明质酸以自分泌/旁分泌的方式与其受体（包括受体酪氨酸激酶和CD44变体（CD44v））一起作用，增强和支持肿瘤上皮细胞的存活。透明质酸、CD44v9变体和基质源性生长因子/细胞因子的过度表达是包括前列腺癌在内的许多癌症的特异性特征。雄激素/雄激素受体相互作用在调节前列腺癌生长中起关键作用。我们之前的研究表明：1)正常上皮细胞中透明质酸合成的增加促进了CD44变体的表达；2)透明质酸与CD44v6-v9相互作用促进受体酪氨酸激酶活化，刺激磷脂酰肌醇3-激酶诱导的细胞存活途径；3) CD44v6/短发夹RNA在体内降低结肠肿瘤的生长（Misra， S., Hascall， V. C., De Giovanni， C., Markwald， R. R., Ghatak， S., 2009） J.生物学杂志。化学，284,12432-12446)。我们的研究结果表明，与前列腺癌细胞相关的肌成纤维细胞合成的肝细胞生长因子可诱导hgf受体/cMet的激活，并刺激透明质酸/CD44v9信号传导。这反过来又稳定了前列腺癌细胞中的雄激素受体功能。基质来源的HGF诱导脂质筏相关信号复合物，该复合物包含CD44v9、cMet/磷脂酰肌醇3-激酶、HSP90和雄激素受体。CD44v9/短发夹RNA逆转复合物中这些成分的组装并抑制雄激素受体的功能。我们的研究结果为透明质酸/ cd44v9调节的雄激素受体功能及其在前列腺癌细胞中的恶性活动提供了新的见解。本研究描述了一个生理相关的体外模型，用于研究前列腺癌发生过程中基质来源的HGF和透明质酸影响分泌上皮中雄激素受体和CD44功能的分子机制。
The main aim of our study is to determine the significance of the stromal microenvironment in the malignant behavior of prostate cancer. The stroma-derived growth factors/cytokines and hyaluronan act in autocrine/paracrine ways with their receptors, including receptor-tyrosine kinases and CD44 variants (CD44v), to potentiate and support tumor epithelial cell survival. Overexpression of hyaluronan, CD44v9 variants, and stroma-derived growth factors/cytokines are specific features in many cancers, including prostate cancer. Androgen/androgen receptor interaction has a critical role in regulating prostate cancer growth. Our previous study showed that 1) that increased synthesis of hyaluronan in normal epithelial cells promotes expression of CD44 variants; 2) hyaluronan interaction with CD44v6-v9 promotes activation of receptor-tyrosine kinase, which stimulates phosphatidylinositol 3-kinase-induced cell survival pathways; and 3) CD44v6/short hairpin RNA reduces colon tumor growth in vivo (Misra, S., Hascall, V. C., De Giovanni, C., Markwald, R. R., and Ghatak, S. (2009) J. Biol. Chem. 284, 12432–12446). Our results now show that hepatocyte growth factor synthesized by myofibroblasts associated with prostate cancer cells induces activation of HGF-receptor/cMet and stimulates hyaluronan/CD44v9 signaling. This, in turn, stabilizes the androgen receptor functions in prostate cancer cells. The stroma-derived HGF induces a lipid raft-associated signaling complex that contains CD44v9, cMet/phosphatidylinositol 3-kinase, HSP90 and androgen receptor. CD44v9/short hairpin RNA reverses the assembly of these components in the complex and inhibits androgen receptor function. Our results provide new insight into the hyaluronan/CD44v9-regulated androgen receptor function and the consequent malignant activities in prostate cancer cells. The present study describes a physiologically relevant in vitro model for studying the molecular mechanisms by which stroma-derived HGF and hyaluronan influence androgen receptor and CD44 functions in the secretory epithelia during prostate carcinogenesis.