LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial-mesenchymal transition
LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial-mesenchymal transition
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DOI：
10.1042/bsr20181165
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发表时间：
2019-01-31
影响因子：
4
通讯作者：
Zhou, Yubo
中科院分区：
文献类型：
--
作者：
Li, Wei;Zhou, Yubo
瘤内缺氧是实体癌的一个众所周知的特征，是癌症转移和包括黑色素瘤在内的不良预后的主要原因。富含亮氨酸的重复序列和 Ig 样结构域 1 (LRIG1) 参与了多种肿瘤的侵袭性进展，其表达经常下降。在本研究中，缺氧暴露加剧了黑色素瘤细胞的侵袭、迁移、血管生成拟态（VM）和上皮间质转化（EMT）。在此过程中，LRIG1表达也降低。重要的是，LRIG1 的过度表达显着抵消了缺氧诱导的侵袭、迁移和 VM，并且在 LRIG1 抑制后进一步增强。机制分析证实，LRIG1 升高通过抑制 E-钙粘蛋白表达和增加 N-钙粘蛋白表达来抑制缺氧诱导的 EMT。相反，停止 LRIG1 进一步增强缺氧引发的 EMT。此外，缺氧刺激激活了表皮生长因子受体 (EGFR)/ERK 通路，该通路因 LRIG1 上调而受到抑制，但因 LRIG1 抑制而进一步激活。更重要的是，用其拮抗剂厄洛替尼阻断该通路可消除 LRIG1 抑制诱导的 EMT，以及随后缺氧条件下黑色素瘤细胞的细胞侵袭、迁移和 VM。总之，这些发现表明 LRIG1 过表达可以通过调节 EGFR/ERK 介导的 EMT 过程来抑制细胞侵袭、迁移和 VM，从而拮抗缺氧引起的侵袭性转移表型。因此，这些发现可能为黑色素瘤治疗提供有希望的靶点。
Intratumoral hypoxia is a well-known feature of solid cancers and constitutes a major contributor to cancer metastasis and poor outcomes including melanoma. Leucine-rich repeats and Ig-like domains 1 (LRIG1) participate in the aggressive progression of several tumors, where its expression is frequently decreased. In the present study, hypoxia exposure aggravated melanoma cell invasion, migration, vasculogenic mimicry (VM), and epithelial-mesenchymal transition (EMT). During this process, LRIG1 expression was also decreased. Importantly, overexpression of LRIG1 notably counteracted hypoxia-induced invasion, migration, and VM, which was further augmented after LRIG1 inhibition. Mechanism analysis corroborated that LRIG1 elevation muted hypoxia-induced EMT by suppressing E-cadherin expression and increasing N-cadherin expression. Conversely, cessation of LRIG1 further potentiated hypoxia-triggered EMT. Additionally, hypoxia stimulation activated the epidermal growth factor receptor (EGFR)/ERK pathway, which was dampened by LRIG1 up-regulation but further activated by LRIG1 inhibition. More important, blocking this pathway with its antagonist erlotinib abrogated LRIG1 suppression-induced EMT, and subsequently cell invasion, migration, and VM of melanoma cells under hypoxia. Together, these findings suggest that LRIG1 overexpression can antagonize hypoxia-evoked aggressive metastatic phenotype by suppressing cell invasion, migration, and VM via regulating EGFR/ERK-mediated EMT process. Therefore, these findings may provide a promising target for melanoma therapy.