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

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 FazioLucia Anna Muscarella

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume20
Issue number10
DOIs
Publication statusPublished - May 23 2019

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Neuroendocrine Tumors
Carcinoid Tumor
lungs
Tumors
Methylation
tumors
Deregulation
Genes
Cells
Lung
genes
methylation
cultured cells
Cell Line
Neoplasms
Messenger RNA
Loss of Heterozygosity
loci
mutations
Cell- and Tissue-Based Therapy

Keywords

  • KEAP1
  • Lung Carcinoid
  • methylation
  • mutation
  • NRF2
  • outcome

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors. / Sparaneo, Angelo; Fabrizio, Federico Pio; la Torre, Annamaria; Graziano, Paolo; Di Maio, Massimo; Fontana, Andrea; Bisceglia, Michele; Rossi, Antonio; Pizzolitto, Stefano; De Maglio, Giovanna; Tancredi, Antonio; Grimaldi, Franco; Balsamo, Teresa; Centra, Flavia; Manzorra, Maria Carmina; Trombetta, Domenico; Pantalone, Angela; Bonfitto, Antonio; Maiello, Evaristo; Fazio, Vito Michele; Muscarella, Lucia Anna.

In: International Journal of Molecular Sciences, Vol. 20, No. 10, 23.05.2019.

Research output: Contribution to journalArticle

Sparaneo, A, Fabrizio, FP, la Torre, A, Graziano, P, Di Maio, M, Fontana, A, Bisceglia, M, Rossi, A, Pizzolitto, S, De Maglio, G, Tancredi, A, Grimaldi, F, Balsamo, T, Centra, F, Manzorra, MC, Trombetta, D, Pantalone, A, Bonfitto, A, Maiello, E, Fazio, VM & Muscarella, LA 2019, 'Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors', International Journal of Molecular Sciences, vol. 20, no. 10. https://doi.org/10.3390/ijms20102531
Sparaneo, Angelo ; Fabrizio, Federico Pio ; la Torre, Annamaria ; Graziano, Paolo ; Di Maio, Massimo ; Fontana, Andrea ; Bisceglia, Michele ; Rossi, Antonio ; Pizzolitto, Stefano ; De Maglio, Giovanna ; Tancredi, Antonio ; Grimaldi, Franco ; Balsamo, Teresa ; Centra, Flavia ; Manzorra, Maria Carmina ; Trombetta, Domenico ; Pantalone, Angela ; Bonfitto, Antonio ; Maiello, Evaristo ; Fazio, Vito Michele ; Muscarella, Lucia Anna. / Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors. In: International Journal of Molecular Sciences. 2019 ; Vol. 20, No. 10.
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T1 - Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors

AU - Sparaneo, Angelo

AU - Fabrizio, Federico Pio

AU - la Torre, Annamaria

AU - Graziano, Paolo

AU - Di Maio, Massimo

AU - Fontana, Andrea

AU - Bisceglia, Michele

AU - Rossi, Antonio

AU - Pizzolitto, Stefano

AU - De Maglio, Giovanna

AU - Tancredi, Antonio

AU - Grimaldi, Franco

AU - Balsamo, Teresa

AU - Centra, Flavia

AU - Manzorra, Maria Carmina

AU - Trombetta, Domenico

AU - Pantalone, Angela

AU - Bonfitto, Antonio

AU - Maiello, Evaristo

AU - Fazio, Vito Michele

AU - Muscarella, Lucia Anna

PY - 2019/5/23

Y1 - 2019/5/23

N2 - 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.

AB - 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.

KW - KEAP1

KW - Lung Carcinoid

KW - methylation

KW - mutation

KW - NRF2

KW - outcome

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DO - 10.3390/ijms20102531

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