Epidermal Growth Factor Receptor-GEP100-Arf6 Axis Affects the Prognosis of Lung Adenocarcinoma

Abstract

The overexpression of Arf6 and GEP100 is responsible for the invasive activity that is crucial for the activation of the epidermal growth factor receptor (EGFR) signaling pathways in human cancer. However, whether or not the expression of the EGFR-GEP100-Arf6 axis can be used as a biomarker for the prognosis of lung cancer has yet to be fully determined. Tumor specimens were collected from 182 patients who underwent a complete resection for lung adenocarcinoma. We analyzed phospho-EGFR (p-EGFR), GEP100, and Arf6 expression levels in the primary tumor by immunohistochemical analysis. The expression of p-EGFR, GEP100, and Arf6 was observed in 65 (35.7%), 95 (52.2%), and 20 (11.0%) patients, respectively. Significant associations between p-EGFR and GEP100 expression and vessel invasion were identified. The expression of these individual molecules was not associated with any statistically significant differences in survival. However, triple positive expression of p-EGFR, GEP100, and Arf6 was significantly associated with an increased risk of death based on the multivariate analysis. The EGFR-GEP100-Arf6 axis affected the prognosis of patients with primary lung adenocarcinoma. The combination of p-EGFR, GEP100, and Arf6 staining can predict the prognosis of patients after surgery.

Pathological functions of the small GTPase Arf6 in cancer progression: Tumor angiogenesis and metastasis

“… 12,13 In lung adenocarcinoma, triple positive expression of Arf6, phosphorylated epidermal growth factor receptor (EGFR) and the Arf6 GEF BRAG2/GEP100 is intimately associated with the increased risk of patient death. 14 Furthermore, a direct correlation between Arf6 protein expression levels and breast cancer invasiveness has been elucidated in a series of breast cancer cell lines with different invasive abilities. 15 Consistent with this observation, siRNA-mediated knockdown of Arf6 in breast cancer, melanoma and glioma cells significantly suppresses their invasiveness.…”

The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective

“…Moreover, ARF3 overexpression promotes breast cancer cell proliferation by regulating the cellcycle G1/S transition, through inhibition of FOXO1 transcription factor activity . Additionally, ARF3 was found to be a candidate gene involved in the progression of Olstad et al, 2003;Ma et al, 2005;Kannangai et al, 2007;Tsai et al, 2012;Schlienger et al, 2015;Davis et al, 2016;Gu et al, Woo et al, 2009;Bidkhori et al, 2013;Howley et al, 2018;Wu Q. et al, 2018ARF6 ↑ Breast, Gastric, Glioma, Liver, Lung, Melanoma, Pancreatic, Prostate, Renal Cell Carcinoma Hashimoto et al, 2004Hu et al, 2009;Knizhnik et al, 2011;Oka et al, 2014;Morgan et al, 2015;Zhang et al, 2015;Hashimoto et al, 2016;Liang et al, 2017; Fujii et al, 2014;Guo et al, 2015;Fujii et al, 2016;Hu et al, 2018;Chen et al, 2019;Harada et al, 2019;Isono et al, Calin et al, 2005;Petrocca et al, 2006;Yendamuri et al, 2008;Siltanen et al, pregnancy-associated breast cancer, based on integrated analysis of microarray profile datasets (Zhang et al, 2019).…”

“…Furthermore, ARF6 silencing impairs invasion of breast cancer, melanoma and glioma (Hashimoto et al, 2004;Hu et al, 2009;Grossmann et al, 2014), providing evidence that ARF6 is an important driver of cancer cell invasion and metastasis. In lung adenocarcinoma, the combined expression of ARF6, its GEF BRAG2/GEP100 and EGFR is associated with decreased patient survival (Oka et al, 2014). ARF6 is known to recruit actin binding proteins, adhesion molecules and proteases, which are essential for invadopodia formation and ExtraCellular Matrix (ECM) degradation (Schweitzer et al, 2011).…”

“…After BRAG2 binding to phosphorylated EGFR, ARF6 is activated in breast cancer cells, leading to the formation of invadopodia with recruitment of Cortactin, Paxillin and the ARF GAP ASAP1 (Onodera et al, 2005;Morishige et al, 2008). In lung adenocarcinoma, the pathway involving EGFR, ARF6 and ASAP1 was reported to be associated with reduced patient survival (Oka et al, 2014). In melanoma cells, the stimulation of WNT5A, a member of the Wnt signaling pathway, induces ARF6 activation mediated by BRAG2, which facilitates the release of β-catenin from cadherin and stimulates tumor cell invasion (Grossmann et al, 2014).…”

Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

“…More recently, depletion of IQSec1 was shown to slow focal adhesion disassembly in keratinocytes (Yue et al, 2014) and also inhibit vasculogenesis in vivo (Manavski et al, 2014). IQSec1 has also been implicated in the metastasis of breast (Morishige et al, 2008), lung (Oka et al, 2014), pancreatic (Xie et al, 2012) cancers, and melanoma (Yoo et al, 2016). While all of these studies highlight a vital role for IQSec1 in cell migration and invasion, we still do not know how IQSec1 mediates these processes.…”