a Barts Cancer Institute , Queen Mary University of London , London , UK.
b Institute of Health and Biomedical Innovation , Queensland University of Technology (QUT) , Brisbane , Australia.
Expert Opin Ther Targets. 2018 Sep;22(9):745-763. doi: 10.1080/14728222.2018.1512587. Epub 2018 Sep 6.
Aberrant levels of kallikrein-related peptidases (KLK1-15) have been linked to cancer cell proliferation, invasion and metastasis. In ovarian cancer, the KLK proteolytic network has a crucial role in the tissue and tumor microenvironment. Publically available ovarian cancer genome and expression data from multiple patient cohorts show an upregulation of most KLKs. Areas covered: Here, we review the expression levels of all 15 members of this family in normal and ovarian cancer tissues, categorizing them into highly and moderately or weakly expressed KLKs, and their association with patient prognosis and survival. We summarize their tumor-biological functions determined in cell-based assays and xenograft models, further highlighting their suitability as cancer biomarkers and attractive candidates for drug development. Finally, we discuss some different pharmaceutical approaches, including peptide-based and small molecule inhibitors, cyclic peptides, depsipeptides, engineered natural inhibitors, antibodies, RNA/DNA-based aptamers, prodrugs, miRNA and siRNA. Expert opinion: In light of the results from clinical and tumor-biological studies, together with the available pharmaceutical tools, we suggest KLK4, KLK5, KLK6 and possibly KLK7 as preferred targets for inhibition in ovarian cancer.
丝氨酸蛋白酶家族 13（KLK1-15）的异常表达与癌细胞的增殖、侵袭和转移有关。在卵巢癌中，KLK 蛋白水解网络在组织和肿瘤微环境中起着关键作用。从多个患者队列获得的公开卵巢癌基因组和表达数据显示大多数 KLKs 上调。
在这里，我们综述了这个家族的 15 个成员在正常和卵巢癌组织中的表达水平，将它们分为高表达和中或低表达 KLKs，并探讨它们与患者预后和生存的关系。我们总结了在基于细胞的测定和异种移植模型中确定的它们的肿瘤生物学功能，进一步强调了它们作为癌症生物标志物的适用性以及作为药物开发有吸引力的候选物。最后，我们讨论了一些不同的药物研发方法，包括基于肽和小分子抑制剂、环肽、环二肽、工程天然抑制剂、抗体、基于 RNA/DNA 的适体、前药、miRNA 和 siRNA。
鉴于临床和肿瘤生物学研究的结果，以及现有的药物研发工具，我们建议将 KLK4、KLK5、KLK6 和可能的 KLK7 作为卵巢癌抑制的首选靶点。
