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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.

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LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial–mesenchymal transition