Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2019 May 26

PMID 31126053

Citations 13

Authors

Angelo Sparaneo

Federico Pio Fabrizio

Annamaria la Torre

Paolo Graziano

Massimo Di Maio

Andrea Fontana

Michele Bisceglia

Antonio Rossi

Stefano Pizzolitto

Giovanna De Maglio

Antonio Tancredi

Franco Grimaldi

Teresa Balsamo

Flavia Centra

Maria Carmina Manzorra

Domenico Trombetta

Angela Pantalone

Antonio Bonfitto

Evaristo Maiello

Vito Michele Fazio

Lucia Anna Muscarella

Affiliations

Soon will be listed here.

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 and genes and promoter hypermethylation, but these two genes have been rarely investigated in low/intermediate grade neuroendocrine tumors of the lung.

Methods: The effects of 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 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 silencing induces an upregulation of NRF2 and some of its targets and that there is a direct correlation between methylation and its mRNA levels. A hypermethylation and Loss of Heterozygosity at gene locus was also observed in nearly half of lung carcinoids.

Conclusions: This is the first study that has described the effects of 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.

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