Elevated expression of the membrane-anchored serine protease TMPRSS11E in NSCLC progression

TMPRSS11E was found to be upregulated in human nonsmall cell lung cancer samples (NSCLC) and cell lines, and high expression was associated with poor survival of NSCLC patients. The results of in vitro and in vivo experiments showed that overexpressing TMPRSS11E resulted in A549 cell proliferation and migration promotion, while the TMPRSS11E S372A mutant with the mutated catalytic domain lost the promoting function. In addition, in mouse xenograft models, silencing TMPRSS11E expression inhibited the growth of 95D cell-derived tumors. To explore the mechanism of marked upregulation of TMPRSS11E in NSCLC cells, promoter analysis, EMSA, and ChIP assays were performed. STAT3 was identified as the transcription factor responsible for TMPRSS11E transcription. Moreover, the purified recombinant TMPRSS11E catalytic domain exhibited enzymatic activity for the proteolytic cleavage of PAR2. Recombinant TMPRSS11E catalytic domain incubation further activated the PAR2-EGFR-STAT3 pathway. These findings established a mechanism of TMPRSS11E-PAR2-EGFR-STAT3 positive feedback, and the oncogenic role of TMPRSS11E as a PAR2 modulator in NSCLC was revealed.