Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice

Nitzki, Frauke; Zibat, Arne; Frommhold, Anke; Schneider, André; Schulz‐Schaeffer, Walter; Braun, Thomas; Hahn, Heidi

doi:10.1038/onc.2011.157

Cited by 27 publications

(28 citation statements)

References 39 publications

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“…The molecular pathogenesis of the embryonal RMS is less clear, although allelic loss at chromosome 11p15, a locus overlapping with a Beckwith-Wiedemann syndrome critical region [8], was reported [9], and aberrant activation of the Sonic Hedgehog pathway was linked to the embryonal RMS in mice [10, 11]. Both forms of RMS are thought to be derived from myogenic progenitors as the consequence of impaired differentiation due to genetic lesions [12-14]. Current conventional treatments for RMS show varying prognostic outcomes, depending on the location of the tumor [1].…”

Section: Introductionmentioning

confidence: 99%

MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis

Huang

Hua

et al. 2014

Oncotarget

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Rhabdomyosarcoma (RMS) is a childhood malignant soft tissue cancer that is derived from myogenic progenitors trapped in a permanent mode of growth. Here, we report that miR-214 is markedly down-regulated in human RMS cell lines. Although not required for embryogenesis in mice, miR-214 suppresses mouse embryonic fibroblast (MEF) proliferation. When re-introduced into RD cells, a line of human embryonal RMS cells, miR-214 showed inhibition of tumor cell growth, induction of myogenic differentiation and apoptosis, as well as suppression of colony formation and xenograft tumorigenesis. We show that in the absence of miR-214, expression of proto-oncogene N-ras is markedly elevated in miR-214−/− MEFs, and manipulations of miR-214 levels using microRNA mimics or inhibitor in RD cells reciprocally altered N-ras expression. We further demonstrate that forced expression of N-ras from a cDNA that lacks its 3'-untranslated region neutralized the pro-myogenic and anti-proliferative activities of miR-214. Finally, we show that N-ras is a conserved target of miR-214 in its suppression of xenograft tumor growth, and N-ras expression is up-regulated in xenograft tumor models as well as actual human RMS tissue sections. Taken together, these data indicate that miR-214 is a bona fide suppressor of human RMS tumorigensis.

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Section: Introductionmentioning

confidence: 99%

MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis

Huang

Hua

et al. 2014

Oncotarget

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“…Mice heterozygous for the Hh receptor Ptch develop embryonal subtype-like RMS [12–14]. Therefore, these mice present a suitable model for the preclinical evaluation of Hh pathway antagonists in the treatment of ERMS, in which Hh signaling is active.…”

Section: Introductionmentioning

confidence: 99%

Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in thePatchedMouse Model of Embryonal Rhabdomyosarcoma

Uhmann

Niemann

Lammering

et al. 2012

Sarcoma

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Aberrant Hedgehog (Hh) signaling is characteristic of the embryonal subtype (ERMS) and of fusion-negative alveolar RMS. In the mouse, ERMS-like tumors can be induced by mutations in the Hh receptor Patched1 (Ptch). As in humans these tumors show increased Hh pathway activity. Here we demonstrate that the treatment with the active form of vitamin D3, calcitriol, inhibits Hh signaling and proliferation of murine ERMSin vivoandin vitro. Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth inPtch-mutant mice, which is, however, a rather late response. Taken together, our results suggest that exogenous supply of calcitriol could be beneficial in the treatment of RMS, especially in those which are associated with aberrant Hh signaling activity.

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“…It has been recently suggested that p53 inactivation could lead to the induction of IGF2 and to the production of immature pluripotent stem cells [33]. Rhabdomyosarcoma could originate from such increased uncommitted precursors, as suggested by data on the Ptch rhabdomyosarcoma model [34], through the interaction with HER-2 expression. HER-2 is best known for its involvement in breast cancer, however it has major functions in muscle cells, for example it is required for the survival of human myoblasts [35], and is frequently expressed in human rhabdomyosarcoma [11].…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor genes promote rhabdomyosarcoma progression in p53 heterozygous, HER-2/neu transgenic mice

et al. 2013

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Human sarcomas arise suddenly, thus preempting the study of preneoplastic and early neoplastic lesions. To explore the natural history of these tumors we studied male mice carrying a heterozygous deletion of p53 and an activated HER-2/neu transgene (BALB-p53Neu mice), that develop urethral rhabdomyosarcomas with nearly full penetrance and early onset (4 months of age). Among genes prominently upregulated in preneoplastic tissue, and more highly expressed in tumors, we found the insulin-like growth factor 2 (Igf2) and tumor suppressors, p19Arf and p21Cip1. In urethral tissues of male mice p53 was less expressed than in female mice, whereas HER-2/neu was more expressed, a combination not found in other skeletal muscles of the same mice that could contribute to the anatomic and sexual specificity of BALB-p53Neu rhabdomyosarcoma. Upregulation of p19Arf and p21Cip1 was additively determined by HER-2/neu activation and by p53 inactivation. Silencing of p19Arf or p21Cip1 in rhabdomyosarcoma cell lines can inhibit cell growth and motility, thus suggesting that these genes can contribute to growth autonomy and malignancy of tumor cells. In vivo injection of gene-silenced cells highlighted selective variations in organ-specific metastatic ability, indicating that overexpression of p19Arf and p21Cip1 controlled both tumor cell-intrinsic properties and microenvironmental interactions. The onset of pelvic rhabdomyosarcoma in BALB-p53Neu male mice is triggered by the coincidental overexpression of HER-2/neu and hypoexpression of the residual p53 allele, that foster p53 loss, Igf2 autocriny and overexpression of p19Arf and p21Cip1, a phenotype that could provide novel potential targets for cancer prevention and therapy.

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Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice

Cited by 27 publications

References 39 publications

MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis

MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis

Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in thePatchedMouse Model of Embryonal Rhabdomyosarcoma

Tumor suppressor genes promote rhabdomyosarcoma progression in p53 heterozygous, HER-2/neu transgenic mice

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