00085472can151883-sup-152525_2_supp_3547228_l91g25.ppt (2.28 MB)

Figure S4 from Heme Oxygenase-1 Controls an HDAC4-miR-206 Pathway of Oxidative Stress in Rhabdomyosarcoma

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posted on 2023-03-30, 23:46 authored by Maciej Ciesla, Paulina Marona, Magdalena Kozakowska, Mateusz Jez, Marta Seczynska, Agnieszka Loboda, Karolina Bukowska-Strakova, Agata Szade, Magdalena Walawender, Magdalena Kusior, Jacek Stepniewski, Krzysztof Szade, Bart Krist, Oleksandr Yagensky, Aleksandra Urbanik, Bernarda Kazanowska, Jozef Dulak, Alicja Jozkowicz

Expression of genes influencing the myoD activity in SMS-CTR eRMS (SMS) and CW9019 aRMS (CW) cell lines cultured in growth medium (GM).

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MNiSW

EU FP POIG

NCBiR

MiR-TANGO IAL

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ARTICLE ABSTRACT

Rhabdomyosarcoma (RMS) is an aggressive soft tissue cancer characterized by disturbed myogenic differentiation. Here we report a role for the oxidative stress response factor HO-1 in progression of RMS. We found that HO-1 was elevated and its effector target miR-206 decreased in RMS cell lines and clinical primary tumors of the more aggressive alveolar phenotype (aRMS). In embryonal RMS (eRMS), HO-1 expression was induced by Pax3/7-FoxO1, an aRMS hallmark oncogene, followed by a drop in miR-206 levels. Inhibition of HO-1 by tin protoporphyrin (SnPP) or siRNA downregulated Pax3/7-FoxO1 target genes and induced a myogenic program in RMS. These effects were not mediated by altered myoD expression; instead, cells with elevated HO-1 produced less reactive oxygen species, resulting in nuclear localization of HDAC4 and miR-206 repression. HO-1 inhibition by SnPP reduced growth and vascularization of RMS tumors in vivo accompanied by induction of miR-206. Effects of SnPP on miR-206 expression and RMS tumor growth were mimicked by pharmacologic inhibition of HDAC. Thus, HO-1 inhibition activates an miR-206–dependent myogenic program in RMS, offering a novel therapeutic strategy for treatment of this malignancy. Cancer Res; 76(19); 5707–18. ©2016 AACR.

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Keywords

Carcinogenesis Animal models of carcinogenesis Cell Cycle Signal transduction pathways Pediatric Cancers Sarcomas Soft-tissue sarcoma

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