title: MicroRNA-203 Inversely Correlates with Differentiation Grade, Targets c-MYC, and Functions as a Tumor Suppressor in cSCC.
abstract: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer and a leading cause of cancer mortality among solid organ transplant recipients. MicroRNAs (miR) are short RNAs that regulate gene expression and cellular functions. Here, we show a negative correlation between miR-203 expression and the differentiation grade of cSCC. Functionally, miR-203 suppressed cell proliferation, cell motility, and the angiogenesis-inducing capacity of cSCC cells in vitro and reduced xenograft tumor volume and angiogenesis in vivo. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 showed dramatic changes in gene networks related to cell cycle and proliferation. Transcription factor enrichment analysis identified c-MYC as a hub of miR-203-induced transcriptomic changes in squamous cell carcinoma. We identified c-MYC as a direct target of miR-203. Overexpression of c-MYC in rescue experiments reversed miR-203-induced growth arrest in cSCC, which highlights the importance of c-MYC within the miR-203-regulated gene network. Together, miR-203 acts as a tumor suppressor in cSCC, and its low expression can be a marker for poorly differentiated tumors. Restoration of miR-203 expression may provide a therapeutic benefit, particularly in poorly differentiated cSCC.
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Warangkana
authors.initials: W
authors.lastname: Lohcharoenkal
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Masako
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Lovén
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Florian
authors.initials: F
authors.lastname: Meisgen
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ning Xu
authors.initials: NX
authors.lastname: Landén
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Lapins
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kunal Das
authors.initials: KD
authors.lastname: Mahapatra
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Nissinen
authors.affiliation: Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kähäri
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Mona
authors.initials: M
authors.lastname: Ståhle
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Enikö
authors.initials: E
authors.lastname: Sonkoly
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Arsenian-Henriksson
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: Andor.Pivarcsi@ki.se.
authors.forename: Andor
authors.initials: A
authors.lastname: Pivarcsi
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs