Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea.
School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
BMC Biol. 2020 Jun 3;18(1):60. doi: 10.1186/s12915-020-00787-3.
Epithin/PRSS14, a type II transmembrane serine protease, is an emerging target of cancer therapy because of its critical roles in tumor progression and metastasis. In many circumstances, the protease, through its ectodomain shedding, exists as a soluble form and performs its proteolytic functions in extracellular environments increasing cellular invasiveness. The seemingly functional integrity of the soluble form raises the question of why the protease is initially made as a membrane-associated protein.
In this report, we show that the epithin/PRSS14 intracellular domain (EICD) can be released from the membrane by the action of signal peptide peptidase-like 2b (SPPL2b) after ectodomain shedding. The EICD preferentially localizes in the nucleus and can enhance migration, invasion, and metastasis of epithelial cancer when heterologously expressed. Unbiased RNA-seq analysis and subsequent antibody arrays showed that EICD could control the gene expression of chemokines involved in cell motility, by increasing their promoter activities. Finally, bioinformatics analysis provided evidence for the clinical significance of the intramembrane proteolysis of epithin/PRSS14 by revealing that the poor survival of estrogen receptor (ER)-negative breast cancer patients with high epithin/PRSS14 expression is further worsened by high levels of SPPL2b.
These results show that ectodomain shedding of epithin/PRSS14 can initiate a unique and synchronized bidirectional signal for cancer metastasis: extracellularly broadening proteolytic modification of the surrounding environment and intracellularly reprogramming the transcriptome for metastatic conversion. Clinically, this study also suggests that the intracellular function of epithin/PRSS14 should be considered for targeting this protease for anti-cancer treatment.
Epithin/PRSS14 是一种 II 型跨膜丝氨酸蛋白酶，由于其在肿瘤进展和转移中的关键作用，它是癌症治疗的一个新兴靶点。在许多情况下，蛋白酶通过其细胞外结构域的脱落，以可溶性形式存在，并在细胞外环境中发挥其蛋白水解功能，增加细胞侵袭性。可溶性形式的看似功能完整性提出了这样一个问题，即为什么蛋白酶最初是作为一种膜相关蛋白产生的。
在本报告中，我们表明，Epithin/PRSS14 的细胞内结构域（EICD）可以在细胞外结构域脱落后，通过信号肽肽酶样 2b（SPPL2b）的作用从膜上释放。EICD 优先定位于细胞核内，并且当异源表达时可以增强上皮癌的迁移、侵袭和转移。无偏 RNA-seq 分析和随后的抗体阵列显示，EICD 可以通过增加其启动子活性来控制参与细胞运动的趋化因子的基因表达。最后，生物信息学分析通过揭示高表达 Epithin/PRSS14 的雌激素受体（ER）阴性乳腺癌患者的生存较差，并且高水平的 SPPL2b 进一步恶化，为 Epithin/PRSS14 的跨膜蛋白水解提供了临床意义的证据。
这些结果表明，Epithin/PRSS14 的细胞外结构域脱落可以为癌症转移启动一种独特而同步的双向信号：细胞外广泛修饰周围环境的蛋白水解修饰，以及细胞内重新编程转移转化的转录组。临床上，这项研究还表明，应该考虑 Epithin/PRSS14 的细胞内功能，以将该蛋白酶作为抗癌治疗的靶点。
