title: Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer.
abstract: Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples.In vitroeffects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.
authors.affiliation: 2nd Department of Medicine, Semmelweis UniversityBudapest, Hungary; "Lendület" Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary.
authors.forename: Vince Kornél
authors.initials: VK
authors.lastname: Grolmusz
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Karászi
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Micsik
authors.affiliation: Department of Immunology, Eötvös Loránd University Budapest, Hungary.
authors.forename: Eszter Angéla
authors.initials: EA
authors.lastname: Tóth
authors.affiliation: "Lendület" Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary; Department of Laboratory Medicine, Semmelweis UniversityBudapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Mészáros
authors.affiliation: "Lendület" Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary; Department of Laboratory Medicine, Semmelweis UniversityBudapest, Hungary; Bionics Innovation CenterBudapest, Hungary.
authors.forename: Gellért
authors.initials: G
authors.lastname: Karvaly
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Barna
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University Budapest, Hungary.
authors.forename: Péter Márton
authors.initials: PM
authors.lastname: Szabó
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Hungary.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Baghy
authors.affiliation: Department of Immunology, Eötvös Loránd University Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Matkó
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Hungary.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.affiliation: 2nd Department of Medicine, Semmelweis University Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.affiliation: 2nd Department of Medicine, Semmelweis UniversityBudapest, Hungary; Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Rácz
authors.affiliation: 2nd Department of Medicine, Semmelweis University Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Igaz
authors.affiliation: "Lendület" Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary; Department of Laboratory Medicine, Semmelweis UniversityBudapest, Hungary; Bionics Innovation CenterBudapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
keywords: Fluorescence activated cell sorting (FACS); adrenocortical cancer (ACC); cell cycle; cell cycle-dependent; chemoresistance; gemcitabine-resistance; malignancy signature; proliferation marker; ribonucleotide reductase; ribonucleotide reductase subunit 2 (RRM2)