The Function And Mechanism Of LncRNA-Dnm3os In Regulates Cell Growth And Cartilage Development

Rhabdomyosarcoma(RMS)is a major 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 force 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.Noonan syndrome is an autosome-dominant inherent abnormalie,affecting skeletal,cardiac,and cognitive development.Currently known genetic lesions are clustered in 7 genes of the RAS signaling pathway,so this syndrome is also referred to as one of the RASopathies.In collaboration with the Children Hospital at Minnesota,USA,we have identified a family of new Noonan syndrome patients carrying a 690 kb deletion at 1q24.3 on chromosome 1.This region contains a long noncoding RNA gene,LncRNA-Dnm3 os.Here we report that Dnm3 os deletion as a novel etiological mechanism associated Noonan syndrome.Previously,mice homozygously null for Dnm3 os were reported to have severe skeletal defects,we postulate that LncRNA-Dnm3 os is essential for endochondral ossification.We proved LncRNA-Dnm3 os promoted the proliferation but suppressed the differentiation of chondrocytes.Further we found that lncRNA-Dnm3 os regulated chondrogenesis independent of the two microRNAs.Thus lncRNA-Dnm3 os is essential for preventing premature differentiation of proliferating chondrocytes that gives rise to the cartilage for future bone formation through endochondral ossification.