A differentiation-based microRNA signature identifies leiomyosarcoma as a mesenchymal stem cell-related malignancy.
Smooth muscle (SM) is a spontaneously contractile tissue that provides physical support and function to organs such as the uterus. Uterine smooth muscle-related neoplasia comprise common well-differentiated benign lesions called leiomyomas (ULM), and rare, highly aggressive and pleomorphic tumors named leiomyosarcomas (ULMS). MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in normal cellular development and tissue homeostasis that can be used to accurately subclassify different tumor types. Here, we demonstrate that miRNAs are required for full smooth muscle cell (SMC) differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs). We also report a miRNA signature associated with this process. Moreover, we show that this signature, along with miRNA profiles for ULMS and ULM, are able to subclassify tumors of smooth muscle origin along SM differentiation. Using multiple computational analyses, we determined that ULMS are more similar to hMSCs as opposed to ULM, which are linked with more mature SMCs and myometrium. Furthermore, a comparison of the SM differentiation and ULMS miRNA signatures identified miRNAs strictly associated with SM maturation or transformation, as well as those modulated in both processes indicating a possible dual role. These results support separate origins and/or divergent transformation pathways for ULM and ULMS, resulting in drastically different states of differentiation. In summary, this work expands on our knowledge of the regulation of SM differentiation and sarcoma pathogenesis.
Danielson
Laura S
LS
Department of Pathology, New York University Medical Center, New York, New York, USA.
Menendez
Silvia
S
Attolini
Camille Stephan-Otto
CS
Guijarro
Maria V
MV
Bisogna
Maria
M
Wei
Jianjun
J
Socci
Nicholas D
ND
Levine
Douglas A
DA
Michor
Franziska
F
Hernando
Eva
E
D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000235:genetics / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D035683:MicroRNAs / Q000145:classification / Q000235:genetics / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000473:pathology / Q000502:physiology; D009215:Myometrium / Q000166:cytology / Q000473:pathology / Q000502:physiology; D010802:Phylogeny; D018235:Smooth Muscle Tumor / Q000235:genetics / Q000473:pathology; D014594:Uterine Neoplasms / Q000235:genetics / Q000473:pathology
D035683:MicroRNAs