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

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.

Claudin-3 Inhibits Lung Squamous Cell Carcinoma Cell Epithelial-mesenchymal Transition and Invasion via Suppression of the Wnt/β-catenin Signaling Pathway

“…In contrast, Zhang et al . have reported that CLND3 expression in AC tissues is upregulated and that CLDN3 overexpression is associated with a poor prognosis 23 . Therefore, we speculated that differential CLDN3 expression in different histological types of lung cancer is related to the origin and development process of tumor cells.…”

“…However, CLDN3 expression is decreased in hepatocellular carcinoma 24 as well as in esophageal SqCC, and loss of CLDN3 expression is associated with the presence of distant metastases 20 . In lung cancer, CLDN3 has been found to be increased in lung AC, but lost in lung SqCC 23 , 25 .…”

“…In another study, the CLDN3 levels were higher in prostate cancer patients with a Gleason score of ≥8, compared to patients with benign prostatic hyperplasia ( p = 0.012) and those with a Gleason score of 6-7 22 . In lung AC, CLDN3 expression increases the malignant potential of lung AC cells, indicating that CLDN3 plays a role in epidermal growth factor receptor activation 23 . However, CLDN3 expression is decreased in hepatocellular carcinoma 24 as well as in esophageal SqCC, and loss of CLDN3 expression is associated with the presence of distant metastases 20 .…”

Identification of potential biomarkers associated with pathogenesis of primary prostate cancer based on meta-analysis approaches

“…More importantly, the EGF-induced overexpression of CLDN3 in adenomacarcinoma (ADC) cells reinforces the cell proliferation (65). In another study CLDN3 was suggested to be a potential molecular target for future application in the treatment of ADC (66). It is interesting that almost all of these cell cycle regulatory proteins can be modulated by PI3K signaling (67).…”

Role of Claudin Proteins in Regulating Cancer Stem Cells and Chemoresistance-Potential Implication in Disease Prognosis and Therapy

“…Since the role of claudins in the regulation of cancer stem cells is well documented, their correlation with drug resistance and distant metastasis is inevitable and obvious [49,88,89]. In brief, claudin-3 and -6 are correlated with lymph node metastasis in squamous cell lung carcinomas [90,91]. Claudin-4 is highly expressed in primary and metastatic prostate cancer [92] and gastric cancer [93,94].…”