Purpose: Highly invasive and metastatic cancer cells, such as adenocarcinoma of the lung cells, form irregular protrusions by assembling a branched network of actin filaments. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2). In this study, colocalization of Arp2 and WAVE2 in adenocarcinoma of the lung was investigated to elucidate its prognostic value. Experimental Design: Immunohistochemical staining of Arp2 and WAVE2 was done on mirror sections of 115 adenocarcinomas of the lung from pathologic stage IA to IIIA classes. KaplanMeier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of the coexpression of Arp2 and WAVE2. Results: Immunoreactivity for both Arp2 andWAVE2 was detected in the same cancer cells in 78 (67.8%) of the 115 lung cancer specimens. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with lymph-node metastasis (P = 0.0046), and significantly lower in bronchioloalveolar carcinomas (P < 0.0001).The patients whose cancer cells coexpressed them had a shorter disease-free survival time (P < 0.0001) and overall survival time (P < 0.0001). Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent risk factor for tumor recurrence. Conclusions: Coexpression of Arp2 and WAVE2 is correlated with poorer patient outcome, and may be involved in the mechanism of cancer metastasis.Cell migration, especially by ameboid movement, plays an essential role in the physiologic function of many organisms, from unicellular organisms, such as the ameba, to complex organisms, such as mammals. Many types of mammalian cells, such as embryonic cells, hematopoietic cells, and fibroblasts, have their own directional motility that maintains their specific role in homeostasis. Migrating cells form cytoplasmic protrusions, such as lamellipodia, filopodia, or microspikes, and malignant cells have abnormal lamellipodia or protrusions known as invadopodia (1, 2). These cytoplasmic protrusions act in a coordinated manner and enable motile cancer cells to migrate, invade, or metastasize.Among the variously shaped protrusions, lamellipodia are thought to play the greatest role in cell motility (1). Lamellipodia are wide but thin in cross section, and this characteristic morphology is due to the construction of branched actin filament arrays within them (3, 4). Actinrelated protein 2 and 3 complex (Arp2/3 complex) and proteins of the Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein (WAVE) family are involved in the process of lamellipodium formation. Arp2/3 complex is located at the forks of branches and enables actin filaments to form branches (5 -7). Thus, the Arp2/3 complex is responsible for the formation of the distinctive structure of lamellipodia and is essential for the moveme...
Abstract. Cigarette smoking not only promotes lung carcinogenesis, but it has also been demonstrated to promote the progression of lung cancer. Despite nicotine being a major component of cigarette smoke, it is not carcinogenic when acting alone. Instead, it is believed to function as a tumor promoter. Due to the fatal consequences of lung cancer being primarily associated with the processes of invasion and metastasis, the present study aimed to determine the effect of nicotine on the migratory activity of lung cancer cells. The effect of nicotine on the migration of lung cancer A549 cells was evaluated by a wound healing assay. Hepatocyte growth factor (HGF) was used as a pro-migratory stimulus. During several of the experiments, specific inhibitors of α7-nicotine acetylcholine receptor (α7-nAchR), phosphoinositide kinase-3 (PI3K) and extracellular signal-related kinase (ERK)1/2 were included. The phosphorylation levels of Akt and ERK1/2 were examined using a cell-based protein phosphorylation assay. It was observed that nicotine did not induce cell migration by itself, but that it instead promoted HGF-induced cell migration. The effects of nicotine were inhibited by the pretreatment of the cells with the α7-nAchR inhibitor, methyllycaconitine, and the PI3K inhibitor, LY294002. The mitogen-activated protein kinase/ERK kinase kinase inhibitor exerted modest, but non-significant inhibitory activity on the effect of nicotine. Nicotine did not induce Akt phosphorylation by itself, but instead promoted the HGF-induced phosphorylation of Akt. It was also observed that nicotine had no effect on ERK1/2 phosphorylation. The results from the present study indicate that nicotine, when alone, does not have a pro-migratory function, but instead enhances responsiveness to the pro-migratory stimulus emitted by HGF. The current study provides an insight into the mechanism of tumor promotion by demonstrating that nicotine and α7-nAchRs act in synergy with the HGF-induced PI3K/Akt signaling pathway, increasing the sensitivity of lung cancer cells to HGF, and thereby promoting cell migration, a vital step in invasion and metastasis. IntroductionLung cancer has one of the lowest survival rates of all types of cancer, accounting for 1.59 million mortalities in the world in 2012 (1). Smoking, particularly of cigarettes, is estimated to cause 87% of the lung cancer mortalities in men, and 70% of the lung cancer mortalities in women (2). Cigarette smoke contains numerous carcinogens, of which, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, are likely to serve major roles (3). However, recent evidence suggests that cigarette smoking not only promotes lung carcinogenesis, but that it also promotes the progression of lung cancer (4). For example, continued smoking during lung cancer treatment has been associated with decreased survival (5), while smoking cessation during the treatment improves the therapeutic outcome (6). Furthermore, cigarette smoking increases the r...
p<0.05). Finally, we showed that eIF4E/eIF4GI KD affected microRNAs critically involved in migration and EMT processes. Conclusion: Our study shows that targeting eIF4E/ eIF4GI reduces migration and EMT, both essential for metastasis, thereby underscoring the role of translation initiation in NSCLC metastatic tumor formation. Understanding the molecular events which promote metastasis and improving the means of foretelling their development is a major goal of current clinical research. We suggest that targeting translation initiation in NSCLC with clinically employed drugs that inhibit eIF4E/eIF4GI (Ribavirin/ 4EGI) may afford a valid and effective therapeutic strategy in NSCLC patients and may diminish lung cancer metastatic spread and morbidity and improve the patient's life quality.
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