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

// Lianmin Zhang 1, * , Yuan Wang 1, * , Bin Zhang 1 , Hua Zhang 1 , Meng Zhou 1 , Mei Wei 1 , Qiuping Dong 1 , Yue Xu 1 , Zhaosong Wang 1 , Liuwei Gao 1 , Yanjun Qu 1 , Bowen Shi 1 , Jinfang Zhu 1 , Yuesong Yin 1 , Yulong Chen 1 , Lu Sun 1 , Wei Zhang 1 , Shilei Xu 1 , Guoguang Ying 1 , Changli Wang 1 1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China * These authors have contributed equally to this work Correspondence to: Changli Wang, email: wangchangli309@163.com Guoguang Ying, email: yingguoguang163@163.com Keywords: adenocarcinoma, tight junction, claudin-3, EGF, proliferation Received: April 22, 2016      Accepted: January 04, 2017      Published: February 01, 2017 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 C LDN3 overexpression in promoting the malignant potential of lung adenocarcinoma. This function is potentially regulated by the EGF-activated MEK/ERK and PI3K-Akt pathways.