University of Oulu

Clinical impact of antioxidant enzymes Prx6 and Trx and their regulators Nrf1 and Nrf2 in diffuse Large B-cell lymphoma

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Author: Kari, Esa1,2,3,4
Organizations: 1University of Oulu Graduate School
2University of Oulu, Faculty of Medicine
3Medical Research Center Oulu
4Oulu University Hospital
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.7 MB)
Persistent link: http://urn.fi/urn:isbn:9789526225289
Language: English
Published: Oulu : University of Oulu, 2020
Publish Date: 2020-03-10
Thesis type: Doctoral Dissertation
Defence Note: Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium 7 of Oulu University Hospital, on 20 March 2020, at 12 noon
Tutor: Professor Outi Kuittinen
Professor Taina Turpeenniemi-Hujanen
Reviewer: Professor Veli-Matti Kosma
Docent Timo Muhonen
Opponent: Professor Anna-Liisa Levonen
Description:

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the single most common lymphoid malignancy in Western world. Excess oxidative stress and antioxidative enzyme expression have previously been associated with adverse disease presentation and poor prognosis in DLBCL. The present study evaluated the clinical relevance of two antioxidant enzymes—peroxiredoxin 6 (Prx6) and thioredoxin-1 (Trx)—, one oxidative stress marker—8-hydroxydeoxyguanosine (8-OHdG)—, and four antioxidative, response-related transcription factors nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2), Kelch ECH associating protein 1 (Keap1) and BTB (broad complex (BR-C), tramtrack (ttk), bric-a-brac/poxvirus (bab)) domain and Cap’n’collar (CNC) homolog 1 (Bach1) in DLBCL patients and cell culture (Trx).

The pre-treatment blood serum levels of Prx6 were found to be significantly lower among DLBCL patients compared to healthy controls, and these levels were observed to rise to the controls’ levels after treatments. Low Prx6 levels were associated with neutropenic infections; thus, Prx6 might be a potential marker for selecting patients to receive white blood cell growth factors.

All tissue assessed transcription factors, excluding Bach1, had prognostic implications among high-risk DLBCL patients. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 were related to poor overall survival. Nuclear Nrf2 and Bach1 expressions were associated with adverse clinical features in DLBCL.

Lymphoma cell’s cytoplasmic Trx expression was associated with superior survival with DLBCL patients who received etoposide-containing, high-dose chemotherapy or R-CHOEP. In the cell culture model, knockdown of Trx resulted in sensitization of lymphoma cells to doxorubicin and decreased the response to etoposide. Trx appears to be predict the response to etoposide (R-CHOEP).

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Tiivistelmä

Diffuusi suurten B-solujen lymfooma (DLBCL) on yleisin yksittäinen imusolmukesyöpä länsimaissa. Runsas oksidatiivinen stressi ja antioksidatiivisten entsyymien ilmentyminen on aiemmin yhdistetty huonoon taudinkuvaan ja ennusteeseen DLBCL:ssä. Tässä tutkimuksessa arvioitiin kahden antioksidatiivisen entsyymin peroksiredoksiini 6 (Prx6) ja tioredoksiini-1 (Trx), yhden oksidatiivisen stressin markkerin 8-hydroksideoksyguanosiinin (8-OHdG) sekä neljän antioksidatiivivasteeseen liittyvän transkriptiotekijän tumafaktori erytoidi 2-liittyvä faktori 1 (Nrf1) ja faktori 2 (Nrf2), Kelch ECH assosioituva proteiini 1 (Keap1) ja BTB (broad complex (BR-C), tramtrack (ttk), bric-a-brac/poxvirus (bab)) domeeni ja Cap’n’collar (CNC) homologi 1 (Bach1) kliinistä merkitystä DLBCL-potilailla sekä soluviljelyssä (Trx).

Hoitoja edeltävien Prx6-seerumipitoisuuksien havaittiin olevan huomattavasti pienempiä verrattuna terveisiin kontrolleihin. Nämä pitoisuudet nousivat hoitojen jälkeen kontrollien tasolle. Matala seerumin Prx6 assosioitui neutropeenisiin infektioihin, minkä vuoksi Prx6 voisi olla potentiaalinen markkeri valkosolukasvutekijän käyttöön.

Kaikilla kudoksesta arvioiduilla transkriptiotekijöillä, pois lukien Bach1, oli ennusteellista merkitystä korkean riskin DLBCL-potilaille. Matala Nrf1-tumaekspressio, korkea Nrf1-sytoplasmaekspressio, korkea Nrf2-tumaekspressio ja matala Keap1-sytoplasmaekspressio liittyivät huonoon kokonaiselinaikaan. Nrf2- ja Bach1-tumaekspressiot assosioituvat huonompaan taudinkuvaan DLBCL:ssä.

Lymfoomasolujen Trx-sytoplasmaekspressio liittyi parempaan ennusteeseen DLBCL-potilailla, jotka saivat hoidoksi etoposidia sisältävän korkea-annoshoidon tai R-CHOEP-kuurin. Soluviljelymallissa Trx:n tuotannon kumoaminen aiheutti lymfoomasolujen herkistymistä doksorubisiinille ja resistenssiä etoposidille. Trx vaikuttaa ennustavan vastetta etoposidille (R-CHOEP-hoidolle).

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Osajulkaisut / Original papers

Osajulkaisut eivät sisälly väitöskirjan elektroniseen versioon / Original papers are not included in the electronic version of the dissertation.

  1. Kari E. J. M., Kuusisto M. E. L., Böhm J., Haapasaari, K.-M., Teppo, H.-R., Karihtala, P., … Kuittinen, O. (2019). Peroxiredoxin 6 Serum Levels and Risk of Neutropenic Infections in Diffuse Large B-cell Lymphoma. Anticancer Research, 39(9), 4925–4931. https://doi.org/10.21873/anticanres.13680

  2. Kari, E., Teppo, H.-R., Haapasaari, K.-M., Kuusisto, M. E. L., Lemma, A., Karihtala, P., … Kuittinen, O. (2019). Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP. Journal of Clinical Pathology, 72(4), 316–321. https://doi.org/10.1136/jclinpath-2018-205584

    Rinnakkaistallennettu versio / Self-archived version

  3. Kari E. J. M., Kuusisto M. E. L., Honkavaara, P., Hakalahti, A., Haapasaari, K.-M., Bloigu, R., … Kuittinen, O. (2020). Thioredoxin-1 as a biological predictive marker for selecting diffuse large B-cell lymphoma patients for etoposide-containing treatment. Manuscript in preparation.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN: 0355-3221
ISSN-E: 1796-2234
ISSN-L: 0355-3221
ISBN: 978-952-62-2528-9
ISBN Print: 978-952-62-2527-2
Issue: 1557
Type of Publication: G5 Doctoral dissertation (articles)
Field of Science: 3122 Cancers
Subjects:
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