Abstract
Background. The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance. In lung tumors the deregulation of this pathway is mainly related to point mutations of KEAP1 and NFE2L2 genes and KEAP1 promoter hypermethylation, but these two genes have been rarely investigated in low/intermediate grade neuroendocrine tumors of the lung. Methods. The effects of KEAP1 silencing on NRF2 activity was investigated in H720 and H727 carcinoid cell lines and results were compared with those obtained by molecular profiling of KEAP1 and NFE2L2 in a collection of 47 lung carcinoids. The correlation between methylation and transcript levels was assessed by 5-aza-dC treatment. Results. We demonstrated that in carcinoid cell lines, the KEAP1 silencing induces an upregulation of NRF2 and some of its targets and that there is a direct correlation between KEAP1 methylation and its mRNA levels. A KEAP1 hypermethylation and Loss of Heterozygosity at KEAP1 gene locus was also observed in nearly half of lung carcinoids. Conclusions. This is the first study that has described the effects of KEAP1 silencing on the regulation of NRF2 activity in lung carcinoids cells. The epigenetic deregulation of the KEAP1/NRF2 by a KEAP1 promoter hypermethylation system appears to be a frequent event in lung carcinoids.
Highlights
The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance
Promoter KEAP1 methylation and point mutations in functional domains of KEAP1 and NFE2L2 genes are firstly reported in NSCLC [3,4] and widely described as a specific signature of aggressiveness in many solid tumors, being correlated with overall survival and response of patients to standard treatments [5,6]
NRF2 activation was determined in H720 cells with transient silencing of the KEAP1 gene
Summary
The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance. The KEAP1 (Kelch-like ECH-associated protein 1)/NRF2 (Nuclear factor (erythroid-derived 2)-like 2) is a master pathway regulator of antioxidants and cellular stress responses and is clearly implicated in neoplastic progression and resistance of tumor cells against chemo- and radio-treatments [1], so the consequent enhancement of NRF2 expression is becoming a new potential target of anticancer therapeutic approaches [2]. In solid tumors, both genetic and epigenetic mechanisms are described to play a significant role in the impairment of KEAP1/NRF2 activity. A lack of evidence suggest an important question that needs to be addressed when considering the alterations of KEAP1-NRF2 pathway in the other lung NETs and the impact of NRF2-related targets in the epigenetic context of lung neuroendocrine carcinoma
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