title: Roles for miR-375 in Neuroendocrine Differentiation and Tumor Suppression via Notch Pathway Suppression in Merkel Cell Carcinoma.
abstract: Dysfunction of key miRNA pathways regulating basic cellular processes is a common driver of many cancers. However, the biological roles and/or clinical applications of such pathways in Merkel cell carcinoma (MCC), a rare but lethal cutaneous neuroendocrine (NE) malignancy, have yet to be determined. Previous work has established that miR-375 is highly expressed in MCC tumors, but its biological role in MCC remains unknown. Herein, we show that elevated miR-375 expression is a specific feature of well-differentiated MCC cell lines that express NE markers. In contrast, miR-375 is strikingly down-regulated in highly aggressive, undifferentiated MCC cell lines. Enforced miR-375 expression in these cells induced NE differentiation, and opposed cancer cell viability, migration, invasion, and survival, pointing to tumor-suppressive roles for miR-375. Mechanistically, miR-375-driven phenotypes were caused by the direct post-transcriptional repression of multiple Notch pathway proteins (Notch2 and RBPJ) linked to cancer and regulation of cell fate. Thus, we detail a novel molecular axis linking tumor-suppressive miR-375 and Notch with NE differentiation and cancer cell behavior in MCC. Our findings identify miR-375 as a putative regulator of NE differentiation, provide insight into the cell of origin of MCC, and suggest that miR-375 silencing may promote aggressive cancer cell behavior through Notch disinhibition.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Karan J
authors.initials: KJ
authors.lastname: Abraham
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Geneviève C
authors.initials: GC
authors.lastname: Paré
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Harriet E
authors.initials: HE
authors.lastname: Feilotter
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada. Electronic address: tronv@smh.ca.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Tron
mesh_terms: D015266:Carcinoma, Merkel Cell / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D051883:Receptor, Notch2 / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; C497764:NOTCH2 protein, human; C497570:RBPJ protein, human; D051883:Receptor, Notch2