Combinations of laminin 5 with PTEN, p-EGFR and p-Akt define a group of distinct molecular subsets indicative of poor prognosis in patients with non-small cell lung cancer

Abstract

Abstract. Laminin 5 (Ln5) is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. This study explored the expression of Ln5 and the role of its relationships with PTEN, phospho-EGFR (p-EGFR) and phospho-Akt (p-Akt) in the prognosis of patients with non-small cell lung cancer (NSCLC). The protein expression of Ln5, PTEN, p-EGFR and p-Akt was assessed by immunohistochemical analysis, and their relationships to prognosis were analyzed. IntroductionLung cancer is the leading cause of cancer-related death in the United States and throughout the world in both men and women (1,2). Due to diagnosis in late disease stages and the poor treatment efficacy of metastatic disease, overall survival is >15% and has not improved substantially in the last 30 years (3). Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR), including gefitinib and erlotinib, have become the standard first-line therapy for patients with advanced non-small cell lung cancers (NSCLCs) harboring activating EGFR mutations (4,5). However, almost all patients eventually develop resistance to EGFR TKIs.Laminin 5 (Ln5, also known as laminin 332) is an extracellular matrix (ECM) protein that plays an important role in cell migration and tumor invasion (6,7). It has a cruciform structure with one long arm and three short arms. The coiled-coil structure of the long arm is formed by three chains (α3, β3 and γ2) covalently linked via interchain disulfide bonds (8). The rod-like regions in the short arms are composed of EGF-like repeats intercalated with globular domains (9). Given the multi-domain architecture of Ln5, it seems conceivable that other receptors in addition to integrins interact with one of its many potential ligand sites to mediate its diverse cellular functions, including activation of EGFR signaling.EGFR is a key mediator of oncogenesis in NSCLCs, with its activation inducing tumor proliferation and growth, angiogenesis, invasion and metastasis, and inhibiting apoptosis (10). Activation of Akt (murine thymoma viral oncogene homolog) is one of the mechanisms that mediate the effects of EGFR (11). The Akt pathway regulates diverse biological functions (12). The tumor-suppressor gene PTEN negatively regulates the PI3K/Akt signaling pathway (13).Interactions between Ln5 and PTEN, phospho-EGFR (p-EGFR) and phospho-Akt (p-Akt) in patients with NSCLC are not well understood at the clinical level.

Clinical significance of fascin-1 and laminin-5 in non-small cell lung cancer

“…Several other groups showed that the fascin-1 expression is significantly associated with the prognoses of NSCLC and may be a useful prognostic indicator (Ling et al, 2015;Luo et al, 2015;Zhao et al, 2015). Niki et al (2002) showed laminin-5 expression at the invasive front of lung adenocarcinomas, and Moriya et al (2001) and An et al (2012) showed that overexpression of laminin-5 may be a useful prognostic factor in patients with NSCLC. Our result showed that the expression of fascin-1 and laminin-5 were related to the relapse of NSCLC in patients, which corroborates previous findings.…”

“…Previous studies have showed that both the expression of fascin-1 and laminin-5 were associated with the invasiveness and prognoses of several cancers, including colorectal (Adams, 2015;Fukazawa et al, 2015), gastric (Saito et al, 2010;Tu et al, 2016), pancreatic (Tsai et al, 2013;Chen et al, 2015) cancers and breast adenocarcinomas (D'Alfonso et al, 2015;Wang et al, 2016). Recently, some authors reported that the expression of fascin-1 and laminin-5 were associated with clinico-pathological characteristics of non-small cell lung cancer (Moriya et al, 2001;Niki et al, 2002;Pelosi et al, 2003;Choi et al, 2006;An et al, 2012;Ling et al, 2015;Luo et al, 2015;Zhao et al, 2015;Liu et al, 2016). However, reports regarding the clinical significance of both the expression and serum levels of fascin-1 and laminin-5 in non-small cell lung cancer are scarce.…”

MRC-5 fibroblast-conditioned medium influences multiple pathways regulating invasion, migration, proliferation, and apoptosis in hepatocellular carcinoma

“…Laminins and integrins are intimately related to cancer progression via interaction with MMPs. Previous studies revealed that laminins A1 and B3 can promote the malignant phenotype of melanoma and non-small cell lung cancer [ 24 , 25 ], and α6, β1, β3, β4 and β7 integrins were essential for cancerous invasion [ 26 – 30 ]. The interaction between MMPs and laminins/integrins has received ample attention, and MMP-2 is believed to be one of the major proteases involved in mesenchymal migration [ 31 – 33 ].…”

Loss of phosphatase and tensin homolog expression correlates with clinicopathological features of non‐small cell lung cancer patients and its impact on survival: A systematic review and meta‐analysis

“…Only one study was a multinational study undertaken in 30 different countries, while the other 18 studies were single‐center studies (14 in Asian countries and 4 in Western countries) . NSCLC trials included either all histological subtypes ( n = 17), or adenocarcinoma (ADC) ( n = 2) . Data related to local advanced disease (stages I–III) comprised three of the 19 NSCLC trials, while 13 studies dealt with any stage (I–IV) .…”

“…All articles, including 2486 patients, listed the relationship between PTEN expression and survival outcome in NSCLC . The combined HR was 0.51 (95% CI 0.42–0.62; P = 0.000, I 2 = 59.5%) for OS in 16 studies (Fig ), but was 0.82 (95% CI 0.26–2.60; P = 0.733, I 2 = 84.7%) for DFS in three studies (Fig ; Table ) .…”