HER2 mediates epidermal growth factor-induced down-regulation of E-cadherin in human ovarian cancer cells
HER2 mediates epidermal growth factor-induced down-regulation of E-cadherin in human ovarian cancer cells
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DOI：
10.1016/j.bbrc.2013.03.062
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发表时间：
2013-04-26
影响因子：
3.1
通讯作者：
Leung, Peter C. K.
中科院分区：
文献类型：
--
作者：
Cheng, Jung-Chien;Qiu, Xin;Leung, Peter C. K.
HER 2的过表达与许多类型的人类癌症的不良预后相关。由于HER 2与其他ErbB受体之间的相互作用，HER 2与EGF家族的配体调节肿瘤进展有关。在卵巢癌中，尽管HER 2扩增与患者预后之间的关系仍存在争议，但HER 2介导的肿瘤进展的潜在分子机制尚未完全了解。我们以前的研究表明，EGF诱导卵巢癌细胞的侵袭通过下调E-cadherin的表达，通过上调其转录抑制因子，蜗牛和蛞蝓。已经显示，HER 2的过表达下调人乳腺上皮细胞中的E-钙粘蛋白表达。然而，HER 2是否介导EGF诱导的E-cadherin下调仍不清楚。在这项研究中，我们研究了HER 2在EGF诱导的E-cadherin下调和细胞侵袭增加中的潜在作用。我们表明，EGF治疗诱导EGFR与HER 2的相互作用，并增加人卵巢癌细胞中HER 2的活化;我们还表明，这些作用被EGFR敲低所减弱。重要的是，用HER 2特异性酪氨酸激酶抑制剂AG 825和HER 2 siRNA治疗减少了Snail和Slug的上调以及EGF对E-cadherin的下调。最后，我们还表明，表皮生长因子诱导的细胞侵袭与HER 2 siRNA治疗减弱。这项研究表明，HER 2在介导EGF对Snail，Slug和E-cadherin表达以及人卵巢癌细胞侵袭力的影响中起重要作用。(C)2013 Elsevier Inc. All rights reserved.
Overexpression of HER2 is correlated with a poor prognosis in many types of human cancers. Due to the interaction between HER2 and other ErbB receptors, HER2 is implicated in the EGF family of ligands-regulated tumor progression. In ovarian cancer, although the relationships between HER2 amplification and patient prognosis remain controversial, the underlying molecular mechanisms of HER2-mediated tumor progression are not fully understood. Our previous studies demonstrated that EGF induces ovarian cancer cell invasion by down-regulating E-cadherin expression through the up-regulation of its transcriptional repressors, Snail and Slug. It has been shown that overexpression of HER2 down-regulates E-cadherin expression in human mammary epithelial cells. However, whether HER2 mediates EGF-induced down-regulation of E-cadherin remains unknown. In this study, we examined the potential role of HER2 in EGF-induced down-regulation of E-cadherin and increased cell invasion. We show that EGF treatment induces the interaction of EGFR with HER2 and increases the activation of HER2 in human ovarian cancer cells; we also show that these effects are diminished by knockdown of EGFR. Importantly, treatment with HER2-specific tyrosine kinase inhibitor, AG825, and HER2 siRNA diminished the up-regulation of Snail and Slug as well as the down-regulation of E-cadherin by EGF. Finally, we also show that EGF-induced cell invasion was attenuated by treatment with HER2 siRNA. This study demonstrates an important role for HER2 in mediating the effects of EGF on Snail, Slug and E-cadherin expression as well as invasiveness in human ovarian cancer cells. (C) 2013 Elsevier Inc. All rights reserved.