Cargando…

Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas

BACKGROUND: Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients. METHODS: The exomes...

Descripción completa

Detalles Bibliográficos
Autores principales: Gao, Hua, Wang, Fei, Lan, Xiaolei, Li, Chuzhong, Feng, Jie, Bai, Jiwei, Cao, Lei, Gui, Songbai, Hong, Lichuan, Zhang, Yazhuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407330/
https://www.ncbi.nlm.nih.gov/pubmed/25884948
http://dx.doi.org/10.1186/s12885-015-1267-0
_version_ 1782367890677170176
author Gao, Hua
Wang, Fei
Lan, Xiaolei
Li, Chuzhong
Feng, Jie
Bai, Jiwei
Cao, Lei
Gui, Songbai
Hong, Lichuan
Zhang, Yazhuo
author_facet Gao, Hua
Wang, Fei
Lan, Xiaolei
Li, Chuzhong
Feng, Jie
Bai, Jiwei
Cao, Lei
Gui, Songbai
Hong, Lichuan
Zhang, Yazhuo
author_sort Gao, Hua
collection PubMed
description BACKGROUND: Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients. METHODS: The exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing. RESULTS: Using stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT–qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence. CONCLUSIONS: PRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1267-0) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4407330
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-44073302015-04-24 Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas Gao, Hua Wang, Fei Lan, Xiaolei Li, Chuzhong Feng, Jie Bai, Jiwei Cao, Lei Gui, Songbai Hong, Lichuan Zhang, Yazhuo BMC Cancer Research Article BACKGROUND: Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients. METHODS: The exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing. RESULTS: Using stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT–qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence. CONCLUSIONS: PRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1267-0) contains supplementary material, which is available to authorized users. BioMed Central 2015-04-12 /pmc/articles/PMC4407330/ /pubmed/25884948 http://dx.doi.org/10.1186/s12885-015-1267-0 Text en © Gao et al.; licensee BioMed Central. 2015 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Gao, Hua
Wang, Fei
Lan, Xiaolei
Li, Chuzhong
Feng, Jie
Bai, Jiwei
Cao, Lei
Gui, Songbai
Hong, Lichuan
Zhang, Yazhuo
Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
title Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
title_full Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
title_fullStr Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
title_full_unstemmed Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
title_short Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
title_sort lower prdm2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407330/
https://www.ncbi.nlm.nih.gov/pubmed/25884948
http://dx.doi.org/10.1186/s12885-015-1267-0
work_keys_str_mv AT gaohua lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT wangfei lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT lanxiaolei lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT lichuzhong lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT fengjie lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT baijiwei lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT caolei lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT guisongbai lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT honglichuan lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas
AT zhangyazhuo lowerprdm2expressionisassociatedwithdopamineagonistresistanceandtumorrecurrenceinprolactinomas