Abstract
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.
Highlights
Lung cancer is responsible for the greatest number of cancer deaths in the U.S for both men and women, with 234,000 new cases and 154,000 deaths estimated in 20181
We further found the association of PRSS3 expression with poor survival to be strengthened in multivariate analysis when adjusting for stage (Table 2), identifying PRSS3 expression as an independent prognostic factor for lung adenocarcinoma (LAC) survival
We showed that knockdown or inhibition of PRSS3/mesotrypsin inhibits LAC cancer cell invasion and proliferation, and that knockdown of kallikrein-related peptidase 5 (KLK5) inhibits LAC cancer cell invasion and proliferation
Summary
Lung cancer is responsible for the greatest number of cancer deaths in the U.S for both men and women, with 234,000 new cases and 154,000 deaths estimated in 20181. An exemplar of the latter mechanism is offered by mesotrypsin; this isoform of the digestive protease trypsin has evolved novel catalytic features enabling it to proteolytically inactivate many endogenous human protease inhibitors that regulate other serine proteases[16,17,18,19] Given this unusual capability, mesotrypsin may influence the activity in vivo of a wide variety of serine proteases, representing a regulatory node in the protease web[16,17]. While the role of mesotrypsin in lung cancer has not been as well-studied, a transcriptional profiling study identified PRSS3 as one of several genes predictive of future distant metastasis and poor survival when expressed in early stage NSCLC tumors[22]. We identify the serine protease kallikrein 5 as a potential mediator in the protease network influenced by mesotrypsin; these two proteases are found to regulate a common, distinctive gene signature responsible for malignant behavior in LAC
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