PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma
PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma
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DOI：
10.1038/s41598-018-38362-0
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发表时间：
2019-02-12
影响因子：
4.6
通讯作者：
Radisky, Evette S.
中科院分区：
文献类型：
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作者：
Ma, Honghai;Hockla, Alexandra;Radisky, Evette S.
丝氨酸蛋白酶被认为是肺癌恶性肿瘤的关键驱动因素和促进因素，虽然这些蛋白质代表了治疗性抑制剂的直接靶点，但这些酶发挥作用的复杂网络使干预的最佳点的鉴定变得复杂。在这里，我们牵连的信号通路组成的PRSS 3/中胰蛋白酶和激肽释放酶相关肽酶5（KLK 5）在肺腺癌恶性肿瘤。我们发现PRSS 3/中胰蛋白酶表达升高是肺腺癌患者预后不良的预后因素，并且PRSS 3/中胰蛋白酶的遗传或药理学靶向降低了肺腺癌细胞的侵袭性和增殖。我们进一步表明，PRSS 3/中胰蛋白酶的已知靶标KLK 5的遗传靶向表型模仿PRSS 3/中胰蛋白酶敲低的作用，并且KLK 5的表达升高对于肺腺癌的结果具有类似的预后。最后，我们使用转录谱实验表明，PRSS 3/中胰蛋白酶和KLK 5控制一个共同的恶性促进途径。这些实验暗示了肺腺癌中潜在的PRSS 3/中胰蛋白酶-KLK 5信号传导模块，并揭示了选择性靶向这些途径的潜在治疗益处。
Serine proteases have been implicated as key drivers and facilitators of lung cancer malignancy, and while these proteins represent straightforward targets for therapeutic inhibitors, identification of optimal points for intervention has been complicated by the complex networks in which these enzymes function. Here we implicate a signaling pathway consisting of PRSS3/mesotrypsin and kallikrein-related peptidase 5 (KLK5) in lung adenocarcinoma malignancy. We show that elevated PRSS3/mesotrypsin expression is prognostic for poor outcome for patients with lung adenocarcinoma, and that genetic or pharmacologic targeting of PRSS3/mesotrypsin reduces lung adenocarcinoma cell invasiveness and proliferation. We further show that genetic targeting of KLK5, a known target of PRSS3/mesotrypsin, phenocopies the effect of PRSS3/mesotrypsin knockdown, and also that elevated expression of KLK5 is similarly prognostic for outcome in lung adenocarcinoma. Finally, we use transcriptional profiling experiments to show that PRSS3/mesotrypsin and KLK5 control a common malignancy-promoting pathway. These experiments implicate a potential PRSS3/mesotrypsin-KLK5 signaling module in lung adenocarcinoma and reveal the potential therapeutic benefit of selectively targeting these pathways.