Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment.
Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment.
复制标题
DOI：
10.1038/jid.2011.190
复制
发表时间：
2011-11
影响因子：
6.5
通讯作者：
Hess, Jochen
中科院分区：
文献类型：
--
作者：
Krenzer, Stefanie;Peterziel, Heike;Mauch, Cornelia;Blaber, Sachiko I.;Blaber, Michael;Angel, Peter;Hess, Jochen
皮肤恶性黑色素瘤是一种预后不良的侵袭性疾病。临床和实验研究为该疾病的发病机制提供了重要的见解，包括黑色素瘤细胞与周围角质形成细胞、成纤维细胞和免疫细胞之间的功能相互作用。然而，转移性黑色素瘤患者预后非常差，临床治疗大多难以治愈。因此，迫切需要新的诊断工具来监测黑色素瘤的发展以及治疗靶点。我们研究了kallikrein相关肽酶6 （KLK6）在人类黑色素瘤组织切片中在肿瘤发展过程中的表达模式。虽然KLK6在肿瘤细胞中未检测到，但我们在良性痣、原发性黑色素瘤和皮肤转移灶附近的角质形成细胞和基质细胞中发现了强烈的KLK6蛋白表达，这表明在肿瘤转化和恶性进展过程中，细胞外KLK6具有旁分泌功能。因此，重组Klk6蛋白显著诱导黑色素瘤细胞迁移和侵袭，同时加速细胞内Ca2+通量。我们可以进一步证明，klk6诱导的细胞内Ca2+通量和肿瘤细胞侵袭严重依赖于蛋白酶激活受体PAR1。我们的数据提供了实验证据，表明KLK6-PAR1轴的特异性抑制可能会干扰肿瘤-微环境相互作用的有害影响，并代表了转译性黑色素瘤研究的潜在选择。
Cutaneous malignant melanoma is an aggressive disease of poor prognosis. Clinical and experimental studies have provided major insight into the pathogenesis of the disease, including the functional interaction between melanoma cells and surrounding keratinocytes, fibroblasts and immune cells. Nevertheless, patients with metastasized melanoma have a very poor prognosis and are largely refractory to clinical therapies. Hence, novel diagnostic tools to monitor melanoma development as well as therapeutic targets are urgently needed. We investigated the expression pattern of the kallikrein-related peptidase 6 (KLK6) in human melanoma tissue sections throughout tumor development. Although, KLK6 was not detectable in tumor cells, we found strong KLK6 protein expression in keratinocytes and stromal cells located adjacent to benign nevi, primary melanomas and cutaneous metastatic lesions, suggesting a paracrine function of extracellular KLK6 during neoplastic transformation and malignant progression. Accordingly, recombinant Klk6 protein significantly induced melanoma cell migration and invasion accompanied by an accelerated intracellular Ca2+-flux. We could further demonstrate that KLK6-induced intracellular Ca2+-flux and tumor cell invasion critically depends on the protease-activated receptor PAR1. Our data provide experimental evidence that specific inhibition of the KLK6-PAR1 axis may interfere with the deleterious effect of tumor-microenvironment interaction and represent a potential option for translational melanoma research.
登录
查看更多内容
影响因子：
4.8
作者：
Angelo, PF;Lima, AR;Juliano, MA
通讯作者：
Juliano, MA
影响因子：
6.4
作者：
Klose, A;Wilbrand-Hennes, A;Hunzelmann, N
通讯作者：
Hunzelmann, N
影响因子：
2.9
作者：
Blaber, SI;Scarisbrick, IA;Blaber, M
通讯作者：
Blaber, M
影响因子：
--
作者：
Melnikova, Vladislava O;Villares, Gabriel J;Bar-Eli, Menashe
通讯作者：
Bar-Eli, Menashe
影响因子：
10.3
作者：
Komatsu, N.;Saijoh, K.;Diamandis, E. P.
通讯作者：
Diamandis, E. P.