Institute of Development, Aging and Cancer, Tohoku University


Seminars and Symposia

IDAC Seminar, 30 September 2015

Secretariat, Alumni Association, IDAC
Date Wednesday,30 September 2015, 17:00~
Room Seminar-shitsu 1, IDAC Research building 7F
Title Novel mechanisms of rhabdomyosarcoma and Duchenne muscular dystrophy:
cross talks between heme oxygenase-1 and microRNAs in muscle stem cells
Speaker Jozef Dulak
Affiliation Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology,
Jagiellonian University, Krakow, Poland
Person-in-charge Yasufumi Sato (Department of Vascular Biology; Ext.8528)   
Secretary:Yasuhiro Suzuki (Department of Vascular Biology; Ext.8532) 
Abstract Recent data indicate for the non-canonical effects of heme oxygenase-1 (HO-1; Hmox1), which are not related to its anti-oxidant and anti-inflammatory activities (1,2). Specifically, we have demonstrated that HO-1 is a potent regulator of micoRNAs generation. High expression of Hmox1 impedes maturation of myoblasts through inhibition of myoD expression and downregulation of myomirs, like miR-1, -133a,b and -206 (3,4). In relation to that effect our recent studies point to HO-1 as an important player in rhabdomyosarcoma (RMS), the tumor presumed to develop due to disturbed myoblast differentiation. HO-1 is elevated while miR-206 is decreased in Pax3/7-FoxO1 translocation-positive alveolar RMS cells (aRMS, more aggressive) or in embryonal RMS cells (eRMS, milder) transfected with Pax3-FoxO1 transgene. Inhibition of HO-1 upregulated miR-206, and facilitated induction of myogenic program in RMS. Accordingly, inhibition of HO-1 in mice reduced growth and vascularization of RMS tumors, while induced expression of miR-206 and myogenic markers. Analysis of clinical tumor samples confirmed the association between elevated HO-1, enhanced vascularization, and decreased miR-206. Interestingly, lack of HO-1 in Hmox1-deficient mice is associated with the accelerated differentiation of the satellite cells, the muscle stem cells, leading potentially to their disappearance with age. Interestingly, in Duchenne muscular dystrophy mice (mdx), the expression of Hmox1 is lowered in satellite cells while miR-206 expression is increased. This may contribute to early exhaustion of satellite cells in mdx mice in comparison to WT animals. Concluding, undisturbed HO-1 is necessary for the proper functioning of skeletal muscle stem cells, and its dysregulation seems to be linked to the pathogenesis of muscle diseases.

1. Dulak J, Jozkowicz A. Novel faces of heme oxygenase-1: mechanisms and therapeutic potentials. Antioxid Redox Signal. 2014; 20:1673-6. doi: 10.1089/ars.2013.5761. Epub 2014 Feb 26.
2. Kozakowska M, Szade K, Dulak J, Jozkowicz A. Role of heme oxygenase-1 in postnatal differentiation of stem cells: a possible cross-talk with microRNAs. Antioxid Redox Signal. 2014 Apr 10;20(11):1827-50. doi: 10.1089/ars.2013.5341.
3. Kozakowska M, Ciesla M, Stefanska A, Skrzypek K, Was H, Jazwa A, Grochot-Przeczek A, Kotlinowski J, Szymula A, Sierpniowska A, Mazan M, Yagensky O, Lemke K, Florczyk U, Zebzda A, Dyduch G, Nowak WN, Szade K, Stepniewski J, Marek M, Derlacz R, Loboda A, Dulak J, Jozkowicz A. Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs. Antioxid Redox Signal. 2012 Jan 15;16(2):113-27.
4. Cieśla M, Dulak J, Józkowicz A. MicroRNAs and epigenetic mechanisms of rhandomyosarcoma development. Int J Biochem Cell Biol. 2014: 53C:482-492. pii: S1357-2725(14)00147-2. doi: 10.1016/j.biocel.2014.05.003.