Epidermal growth factor modulates claudins and tight junctional functions in ovarian cancer cell lines

Abstract

Ovarian adenocarcinomas, like human ovarian surface epithelial cells, form functional tight junctions. Tight junction molecules claudin-3 and claudin-4, which are the receptors of Clostridium perfringens enterotoxin (CPE), are abnormally upregulated in epithelial ovarian cancers of all subtypes including, mucinous cystadenocarcinoma and serous cystadenocarcinoma. Clostridium perfringens enterotoxin may be a novel tumor-targeted therapy for ovarian cancers. In epithelial ovarian cancers, overexpression of epidermal growth factor receptor has been observed and the exogenous ligand EGF induces epithelial-mesenchymal transition in ovarian surface epithelium. Epidermal growth factor (EGF) signaling modulates expression of claudins with changes of fence and barrier functions in various cell types. However, the regulation of tight junctions by EGF in ovarian cancers remains unclear. In the present study, to investigate the mechanisms of the regulation of tight junctions in ovarian cancers, ovarian cancer cell lines mucinous cystadenocarcinoma (MCAS) and serous cystadenocarcinoma (HUOA) were treated with EGF. Epidermal growth factor downregulated claudin-3 in MCAS and claudin-4 in HUOA by inducing degradation of the proteins with changes in structures and functions of tight junctions via the MEK/ERK or PI3K/Akt signaling pathway. In addition, in HUOA but not MCAS, EGF downregulated the cytotoxic effect of CPE via claudin-4. Thus, there were different mechanisms for regulation of claudins by EGF between subtypes of epithelial ovarian cancer cells in vitro. These results indicate that EGF may affect claudins and tight junctional functions in ovarian cancer cells during cancer progression.

Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

“…This receptor is mainly present in the basolateral region and can thus potentially induce neoplastic transformation, as suggested previously [14], [19], [38]. Controversially to our observations, a recent study showed that EGF decreased claudin-3 and -4 via MEK/ERK and/or PI3K/Akt signaling pathways in ovarian cancer cell lines [39]. The reasons for the discrepancy observed are currently unclear but may be related to tissue-specific differences in claudin function or even the tissue microenvironment features, as previously discussed [40].…”

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

“…However, EGF mediated the alternation of claudin protein expression are a great difference and depend on the different cell type and tumor as previous described. For instance, a recent study showed that EGF induced downregulation of CLDN3 in mucinous cystadenocarcinoma via the MEK/ERK or PI3K/Akt signaling pathway by inducing degradation of the TJ proteins with changes in structures and functions [25]. Conversely, upregulation of CLDN3 play fundamental role to promote the development of colorectal cancer, which is potentially regulated by the EGF-activated downstream pathway, ERK1/2 and PI3K-Akt signaling pathways [30].…”

“…For instance, EGF was mediated the upregulation of CLDN 1, 3 and 4, and downregulation of CLDN 2, which increased the force of intercellular barrier in MDCK-II cells [23, 24]. In addition, EGF may also regulate the expression functions of claudins in ovarian and colon cancer cells during cancer development via the EGF-activated ERK1/2 and PI3K-Akt pathways [25, 26]. However, its regulatory mechanism in ADC remains unclear.…”

Claudins Overexpression in Ovarian Cancer: Potential Targets for Clostridium Perfringens Enterotoxin (CPE) Based Diagnosis and Therapy

“…Recently this mechanism of the TJ protein regulation in ovarian cancers was explored by treating both ovarian mucinous and serous cystadenocarcinoma cell lines with EGF [71]. EGF was found to downregulate claudin-3 in mucinous ovarian carcinoma cell lines and claudin-4 in ovarian serous cystadenocarcinoma by inducing the degradation of these proteins with also changes in the structure and function of TJ via the MEK/ERK or PI3K/AKT signaling pathway.…”