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.

中文翻译：

---

胞外丝氨酸蛋白酶Epithin / PRSS14的膜内蛋白水解使其具有细胞内核功能。

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而成为癌症治疗的新兴目标。在许多情况下，蛋白酶通过其胞外域脱落以可溶形式存在，并在细胞外环境中执行其蛋白水解功能，从而增加了细胞的侵袭性。可溶形式的表面功能完整性提出了这样一个问题，即为什么最初将蛋白酶制成膜相关蛋白。在此报告中，我们显示了胞外域脱落后，通过信号肽肽酶样2b（SPPL2b）的作用，可以从膜上释放出epithin / PRSS14细胞内域（EICD）。当异源表达时，EICD优先定位在细胞核中，并且可以增强上皮癌的迁移，侵袭和转移。无偏RNA-seq分析和随后的抗体分析表明，EICD可以通过增加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证明高水平SPPL2b进一步恶化了雌激素受体（ER）阴性的高表皮蛋白/ PRSS14表达的乳腺癌患者的不良生存，为表皮蛋白/ PRSS14膜内蛋白水解的临床意义提供了证据。这些结果表明，epithin / PRSS14的胞外域脱落可引发癌症转移的独特且同步的双向信号：细胞外拓宽周围环境的蛋白水解修饰，并在细胞内重新编程转录组以进行转移转化。临床上