Circulating Proteoglycan Endocan Mediates EGFR-Driven Progression of Non–Small Cell Lung Cancer

Abstract

◥Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of patients with non-small cell lung cancer (NSCLC) with EGFR-mutant tumors, TKI resistance often returns as a result of additional EGFR mutations. In addition to seeking for next-generation EGFR-TKI, developing novel EGFR-targeting strategies may hold the key to overcome the vicious cycle of TKI resistance. Endocan is known as a receptor tyrosine kinase ligand enhancer in tumorigenesis, but the impact of endocan on EGFR-driven NSCLC progression remains unknown. In this study, higher endocan levels were found in lung tumors compared with cancer-free tissues and correlated with poor prognosis in patients with NSCLC harboring mutant EGFR; circulating endocan levels were also significantly higher in patients with mutant EGFR. Endocan facilitated EGFR signaling via direct binding and enhancing of the EGF-EGFR interaction and supported the growth of tumors driven by mutated EGFR. Activated EGFR in turn upregulated expression of endocan via JAK/STAT3 and ERK/ELK cascades, thus forming a positive regulatory loop of endocan-EGFR signaling. On the basis of the binding region between endocan and EGFR, we designed therapeutic peptides and demonstrated promising therapeutic effects in xenografts harboring EGFR mutations including TKI-resistant T790M. Together, our findings highlight the novel interaction between endocan and EGFR and new opportunities to effectively target endocan-EGFR regulatory axis in patients with TKI-resistant NSCLC.Significance: Endocan is a novel and critical regulator of EGF/EGFR signaling and serves as an alternative target of EGFR-TKI resistance in NSCLC.

ESM1/VEGFα/ERK signaling axis augments cell proliferation and tumor angiogenesis in human cervical squamous cell carcinoma

“…ESM1 might promote the progression of HNSC through the Ras-MAPK-ERK signaling pathway [23]. In addition, as a glycoprotein secreted into the bloodstream, ESM1 mediated the progression of EGFR-driven non-small cell lung cancer [35]. Nevertheless, the expression alteration, molecular mechanisms, and biological functions of ESM1 in CSCC remain poorly understood.…”

P2Y2R-Mediated PAK1 Activation Is Involved in ESM-1 Overexpression in RT-R-MDA-MB-231 through FoxO1 Regulation

“…Additionally, RT-R-MDA-MB-231 cells displayed higher expression levels of hypoxia-inducible factor (HIF-1α), activated nuclear factor-κB (NF-κB), and signal transducer and activator of transcription-3 (STAT-3) compared to MDA-MB-231 cells [ 6 , 21 ]. In addition, it has been reported that the transcription factors activator protein-1 (AP-1) and FoxO1 regulate the expression of ESM-1 as transcription factors [ 26 , 27 , 28 , 29 , 30 , 31 ]. Therefore, we sought to determine which transcription factors are involved in ESM-1 overexpression in RT-R-MDA-MB-231 cells.…”

“…In addition, ESM-1 expression has been reported to be enhanced by HIF-1α in response to hypoxia in human colorectal cancer [ 27 ] and to be mediated by NF-κB in IL-1β-induced inflammatory conditions in human chondrocytes [ 28 ]. Furthermore, another study reported that ESM-1 expression was regulated via the JAK/STAT3 pathway in EGFR-activated non-small-cell lung cancer cells [ 29 ] and induced by FoxO1 nuclear localization in cultured endothelial cells under hypoxic conditions [ 31 ]. Importantly, our previous studies showed that the level of HIF-1α and the activities of NF-κB and STAT-3 were induced and associated with tumor development in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells [ 6 , 21 ].…”

EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer

“…Proteoglycans, including serglycin ( 100 ), perlecan ( 101 ), versican ( 102 ), aggrecans ( 103 ), decorin ( 104 ), lumican ( 105 ), syndecans ( 106 ), testicans ( 107 ), endocan ( 108 ), and glypicans ( 109 ) are involved in EGFR signaling pathways in lung cancer ( 108 ). For example, endocan is known to be a RTK ligand enhancer in tumorigenesis.…”

“…Through the Janus kinase (JAK)/STAT3 and ERK/ELK cascades, activated EGFR upregulates endocan expression, creating a positive regulatory loop of endocan-EGFR signaling. These results point to a novel relationship between EGFR and endocan and new strategies to target the endocan-EGFR regulatory axis in NSCLC patients with TKI-resistant (108). Another example is decorin, small leucinerich proteoglycans (SLRP) that control cell growth and migration in several tumor cell lines (104).…”