Human Cancer Biology Hypoxic Activation of the PERK/eIF2a Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3

Purpose: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2a signaling pathway, a component of the unfolded protein response (UPR) and an importantmediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated. ExperimentalDesign:Amplification and expression of LAMP3, a UPRmetastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven