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The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer.
Molecular Oncology ( IF 6.6 ) Pub Date : 2019-11-28 , DOI: 10.1002/1878-0261.12587
Thomas Kryza 1, 2, 3, 4 , Nathalie Bock 1, 2, 3 , Scott Lovell 5 , Anja Rockstroh 1, 2, 3 , Melanie L Lehman 1, 2, 3, 6 , Adam Lesner 7 , Janaththani Panchadsaram 1, 2, 3 , Lakmali Munasinghage Silva 2, 3 , Srilakshmi Srinivasan 1, 2, 3 , Cameron E Snell 4, 8 , Elizabeth D Williams 1, 2, 3 , Ladan Fazli 6 , Martin Gleave 6 , Jyotsna Batra 1, 2, 3 , Colleen Nelson 1, 2, 3 , Edward W Tate 5 , Jonathan Harris 2 , John D Hooper 4, 8 , Judith A Clements 1, 2, 3
Affiliation  

Kallikrein-related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related-signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, SRY-Box 9), particularly an involvement of the mitogen-activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.

中文翻译:

激肽释放酶相关肽酶14的分子功能证明了晚期前列腺癌的关键调节作用。

激肽释放酶相关的肽酶14(KLK14)是参与前列腺癌(PCa)发病机理的几种分泌的KLK丝氨酸蛋白酶之一。尽管相对未被充分研究,但最近的报告已确定KLK14在PCa开发过程中过表达。然而,在PCa进展过程中KLK14表达的调节以及该蛋白酶在前列腺肿瘤微环境中的分子和生物学功能仍然未知。为了确定PCa进展过程中KLK14表达的调节,我们使用可公开获得的数据库和免疫组织化学分析了患者样品中KLK14的表达水平。为了描述PCa进程中涉及KLK14的分子机制,我们整合了蛋白质组学,转录组学和体外测定法,旨在鉴定底物,相关信号通路,和这种蛋白酶的功能作用。我们显示,KLK14表达在晚期PCa中升高,尤其是在转移中。另外,发现与未治疗的患者相比,对新辅助疗法有反应的患者的PCa组织中KLK14水平降低。此外,我们还确定在发展去势抵抗性PCa的患者中会再次出现KLK14表达。蛋白质组学和转录组学分析以及功能测定的结合揭示了几种新的KLK14底物(agrin,desmoglein 2,玻连蛋白,层粘连蛋白)和KLK14调控的基因(Interleukin 32,midkine,SRY-Box 9),特别是有丝分裂原的参与激活的蛋白激酶1和白介素1受体通路,以及KLK14参与细胞迁移的调控,支持其参与PCa进展的侵略性特征。总之,我们的工作表明KLK14表达与侵袭性PCa的发展有关,这表明靶向这种蛋白酶可能提供限制前列腺肿瘤进展的新途径。必须进行其他工作才能确定在PCa中靶向/共靶向KLK14的益处和影响,以及确定将KLK14表达作为PCa侵袭性或对治疗反应的预测指标的潜在用途。
更新日期:2019-11-01
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