Abstract
Chronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in the at-risk for lung cancer pulmonary and the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory. Utilizing a doxycycline-controlled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory. Chromatin immunoprecipitation and methylation-specific PCR further revealed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDH1 (E-cadherin) promoter following the chronic IL-1β exposure. Chemical inhibition of DNA methylation not only restored E-cadherin expression in EMT memory, but also primed cells for chemotherapy-induced apoptosis.
Highlights
Dysregulated inflammation is recognized as one of the hallmarks of cancer and is involved in tumor initiation, progression, and metastasis[1,2,3]
Because IL-1β and IL-1β-induced genes have been implicated in promoting lung tumor progression in multiple experimental settings and human specimens[10,14,15,16,25], we sought to examine whether IL-1β induced Epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)
Because chronic inflammation may play a greater role during tumor development than acute inflammation, we investigated the impact of chronic IL-1β exposure on these tumor cells (Fig. 1B)
Summary
Dysregulated inflammation is recognized as one of the hallmarks of cancer and is involved in tumor initiation, progression, and metastasis[1,2,3] Chronic inflammatory conditions, such as chronic obstructive pulmonary disease or ulcerative colitis, are strongly associated with elevated cancer incidence[4,5,6]. Interleukin-1 beta (IL-1β), a proinflammatory cytokine, correlates with tumor progression in non-small cell lung cancer (NSCLC) patients in multiple studies. A similar conclusion was drawn in an independent study showing that elevated serum IL-1β correlates with poor progression-free survival in NSCLC patients[10]. In another study investigating tumor-associated inflammatory responses in early stage lung cancer, high levels of IL-1β were found to be associated with 3-year mortality in adenocarcinoma[11]. This study reveals distinct molecular events modulating acute and chronic inflammation, enhancing our understanding of the temporal-spatial regulation of EMT during metastasis
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