RT Journal Article
SR Electronic
T1 Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells induces dedifferentiated liposarcoma potency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 293068
DO 10.1101/293068
A1 Yu Jin Kim
A1 Minjung Sung
A1 Dan Bi Yu
A1 Mingi Kim
A1 Ji-Young Song
A1 Kyoung Song
A1 Kyungsoo Jung
A1 Yoon-La Choi
YR 2018
UL http://biorxiv.org/content/early/2018/04/01/293068.abstract
AB Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria of well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, it remains unclear whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis. We examined whether MDM2 and/or CDK4 produce WDLPS/DDLPS using transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that co-overexpression of MDM2 and CDK4 plays key roles in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency compared to sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can develop proliferative DDLPS in vivo. Our results suggest that co-overexpression of MDM2 and CDK4 induces DDLPS tumour potency in transformed human BMSCs by accelerating cell growth and migration and blocking adipogenetic potential incooperation with multiple genetic factors.