Claudin-3 expression increases the malignant potential of lung adenocarcinoma cells: role of epidermal growth factor receptor activation.

Lianmin Zhang,Bin Zhang,Wei Zhang,Jinfang Zhu,Yulong Chen,Yuan Wang,Yue Xu,Qiuping Dong,Changli Wang,Bowen Shi,Zhaosong Wang,Shilei Xu,Meng Zhou,Lu Sun,Guoguang Ying,Yanjun Qu,Mei Wei,Hua Zhang,Lei Gao ,Yuelan Yin

doi:10.18632/oncotarget.14974

Lianmin Zhang, Bin Zhang + Show 18 more

Open Access

https://doi.org/10.18632/oncotarget.14974

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Abstract

Claudins are essential for the formation and maintenance of tight junctions (TJ). The altered expression of claudin proteins has been described in a variety of malignancies. However, the alteration of these proteins in lung adenocarcinoma (ADC) are poorly understood. Therefore, we report, based on the protein expression analysis of a total of 275 patient samples, that claudin-3 (CLDN3) expression is significantly increased in ADC tissues and is associated with cancer progression, correlating significantly with the poor survival of ADC patients (p=0.041&0.029). More importantly, forcing CLDN3 expression in ADC cells without endogenous CLDN3 expression resulted in significant increases in the cell proliferation, anchorage-dependent growth, migration and drug-resistance. In addition, epidermal growth factor (EGF) signaling pathway modulates the expression of claudins in a number of solid tumors. However, the mechanism of tight junction regulation by EGF in ADC remains unclear. To investigate this mechanisms, ADC cell lines were treated with EGF and its inhibitor. EGF unregulated CLDN3 expression via the MEK/ERK or PI3K/Akt signaling pathways and was required for the maintenance of baseline CLDN3 expression. Furthermore, downregulation of CLDN3 expression in ADC cell was found to prevent the EGF-induced increase in cell proliferation. In conclusion, our results demonstrate a novel role of CLDN3 overexpression in promoting the malignant potential of lung adenocarcinoma. This function is potentially regulated by the EGF-activated MEK/ERK and PI3K-Akt pathways.

Highlights

Lung cancer remains the major cause of cancerrelated deaths worldwide [1]
Ikari recently reported that CLDN2 enhances cell colonization and migration in lung adenocarcinoma cell line A549, and CLDN2 may be involved in the regulation of cancer cell motility [16, 17]
CLDN3 expression is significantly upregulated in lung adenocarcinoma and an independent predictor for survival in ADC patients

Summary

Introduction

Lung cancer remains the major cause of cancerrelated deaths worldwide [1]. Lung adenocarcinoma is the most common histological subtype which is increasing in prevalence [2]. Ikari recently reported that CLDN2 enhances cell colonization and migration in lung adenocarcinoma cell line A549, and CLDN2 may be involved in the regulation of cancer cell motility [16, 17]. CLDN3 is involved in the development of acinus and the differentiation of alveolar epithelial cells [18] and its levels varied in different subtypes of lung carcinomas [13, 19]. Compared to lung squamous cell carcinoma (SqCC), an increased expression of CLDN3 was found in ADC [19,20,21]. CLDN3 and CLDN4 are highly overexpression in all subtypes of epithelial ovarian cancers, and these regulation enhances angiogenic effects and invasive properties as well as increased matrix metalloproteinase-2 activity [6]. The underlying mechanisms that regulate the function and expression of CLDN3, in lung adenocarcinoma, are poorly understood

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