Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis
Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis
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DOI：
10.1158/0008-5472.can-14-3297
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发表时间：
2015-07-15
期刊：
影响因子：
11.2
通讯作者：
Lee, Ming-Shyue
中科院分区：
文献类型：
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作者：
Ko, Chun-Jung;Huang, Cheng-Chung;Lee, Ming-Shyue
雄激素信号转导失调和细胞周蛋白水解对于前列腺癌的进展是必需的，但它们之间的联系仍不清楚。在这项研究中，我们展示了膜锚定丝氨酸蛋白酶TMPRSS2如何刺激一个蛋白水解级联反应，该反应介导雄激素诱导的前列腺癌细胞侵袭、肿瘤生长和转移。我们发现，在介导雄激素在前列腺癌中的这种促侵袭作用时，膜型基质金属蛋白酶（matriptase）作为TMPRSS2的底物。此外，我们确定在前列腺癌组织中，TMPRSS2表达水平越高，膜型基质金属蛋白酶的激活水平越高。最后，我们发现TMPRSS2促进前列腺癌肿瘤生长和转移的能力与肿瘤异种移植物中膜型基质金属蛋白酶激活增加以及细胞外基质巢蛋白 - 1和层粘连蛋白β1的降解增强有关。总之，我们的研究结果表明，TMPRSS2通过激活膜型基质金属蛋白酶和破坏细胞外基质来促进前列腺癌细胞的生长、侵袭和转移，这意味着将这两种蛋白酶作为治疗前列腺癌的策略具有潜在意义。（C）2015美国癌症研究协会
Dysregulation of androgen signaling and pericellular proteolysis is necessary for prostate cancer progression, but the links between them are still obscure. In this study, we show how the membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth, and metastasis. We found that matriptase serves as a substrate for TMPRSS2 in mediating this proinvasive action of androgens in prostate cancer. Further, we determined that higher levels of TMPRSS2 expression correlate with higher levels of matriptase activation in prostate cancer tissues. Lastly, we found that the ability of TMPRSS2 to promote prostate cancer tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin beta 1 in tumor xenografts. In summary, our results establish that TMPRSS2 promotes the growth, invasion, and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer. (C)2015 AACR.