PTK2 promotes lung cancer progression via cross-talk regulation between EGFR- and TLR-mediated signaling

Abstract

Abstract Introduction Protein tyrosine kinase 2 (PTK2) plays a pivotal role in various cancers via cross-talk with growth factor signaling pathways. PTK2 is amplified in non-small cell lung cancer (NSCLC). However, the functional role of PTK2 has not been elucidated yet. Here, we report that PTK2 is functionally implicated in epidermal growth factor receptor (EGFR)- and toll-like receptors (TLRs)-mediated signaling for progression of lung cancer. Methods Microarray data of NSCLC tumor tissues and matched normal tissues of 42 NSCLC patients were used to gain insights into associations of PTK2 and EGFR expression with patient’s prognosis and cancer progression. CRISPR-Cas9 gene editing method and cancer progression assay were utilized for functional validation of PTK2 in human A549 and H1299 lung cancer cells. In vitro and in vivo tumorigenic assays were performed using a three-dimensional (3D) tumor spheroid formation and a xenografted NOD scid gamma mouse (NSG, NOD/SCID/IL-2Rγnull) model, respectively. Results Patients with up-regulated PTK2 exhibited a poor prognosis after clinical treatments. Gene set enrichment assay (GSEA) revealed that patients with up-regulated PTK2 exhibited high enrichments of gene sets related to lung cancer progression and EGFR- or TLRs-mediated signaling. The functional association between PTK2 and EGFR or TLRs was verified. PTK2-knockout (KO) lung cancer cells exhibited marked attenuations of cancer progression, and in vivo tumorigenic and metastatic activity in xenografted NSG mice. In response to TLR agonists, EGF, or TLR agonists plus EGF, the severe decreases of 3D-tumor spheroid formation could be observed in PTK2-KO lung cancer cells. We further elucidated the molecular mechanism by which PTK2 regulated the cross-talk between EGFR- and TLRs-mediated signaling. PTK2 specifically regulated their downstream molecules for the activation of NF-κB. Conclusions Up-regulated PTK2 might be a reliable marker for EGFR- or TLRs-induced lung cancer progression in NSCLC patients. It could be potentially considered as a therapeutic target in the field of precision or personalized cancer medicine aiming for NSCLC intervention.