Epidermal growth factor modulates claudins and tight junctional functions in ovarian cancer cell lines
Epidermal growth factor modulates claudins and tight junctional functions in ovarian cancer cell lines
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DOI：
10.1007/s00418-012-0956-x
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发表时间：
2012-04
影响因子：
2.3
通讯作者：
M. Ogawa;T. Kojima;Masayuki Someya;Kazuaki Nomura;A. Takasawa;M. Murata;Satoshi Tanaka;Tsuyoshi Saito;N. Sawada
中科院分区：
文献类型：
--
作者：
M. Ogawa;T. Kojima;Masayuki Someya;Kazuaki Nomura;A. Takasawa;M. Murata;Satoshi Tanaka;Tsuyoshi Saito;N. Sawada
卵巢腺癌与人卵巢表面上皮细胞一样，形成功能性紧密连接。紧密连接分子claudin-3和claudin-4是产气荚膜梭菌肠毒素（Clostridium perfringensenterotoxin，CPE）的受体，在卵巢上皮性癌（包括粘液性囊腺癌和浆液性囊腺癌）中表达异常上调，Clostridium perfringensenterotoxin有望成为卵巢癌的新靶向治疗药物。在上皮性卵巢癌中，已经观察到表皮生长因子受体的过度表达，并且外源性配体EGF诱导卵巢表面上皮的上皮-间质转化。表皮生长因子（EGF）信号转导通过改变各种细胞类型中的栅栏和屏障功能来调节claudins的表达。然而，EGF在卵巢癌中对紧密连接的调节仍不清楚。在本研究中，探讨在卵巢癌中的紧密连接的调节机制，卵巢癌细胞系粘液性囊腺癌（MCAS）和浆液性囊腺癌（HUOA）用EGF处理。表皮生长因子通过MEK/ERK或PI 3 K/Akt信号通路诱导紧密连接蛋白的降解和结构与功能的改变，下调MCAS中的claudin-3和HUOA中的claudin-4。此外，在HUOA而不是MCAS中，EGF通过claudin-4下调CPE的细胞毒性作用。因此，有不同的机制调节上皮性卵巢癌细胞在体外的亚型之间的表皮生长因子的claudins。这些结果表明，EGF可能会影响卵巢癌细胞在癌症进展过程中的claudins和紧密连接功能。
Ovarian adenocarcinomas, like human ovarian surface epithelial cells, form functional tight junctions. Tight junction molecules claudin-3 and claudin-4, which are the receptors ofClostridium perfringensenterotoxin (CPE), are abnormally upregulated in epithelial ovarian cancers of all subtypes including, mucinous cystadenocarcinoma and serous cystadenocarcinoma.Clostridium perfringensenterotoxin 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.