title: miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties.
abstract: Renal cell carcinoma (RCC) is an aggressive disease, with 35% chance of metastasis. The 'cancer stem cell' hypothesis suggests that a subset of cancer cells possess stem cell properties and is crucial in tumor initiation, metastasis and treatment resistance. We isolated RCC spheres and showed that they exhibit cancer stem cell/ tumor initiating cell-like properties including the formation of self-renewing spheres, high tumorigenicity and the ability to differentiate to cell types of the original tumor. Spheres showed increased expression of stem cell-related transcription factors and mesenchymal markers. miRNAs were differentially expressed between RCC spheres and their parental cells. Inhibition of miR-17 accelerated the formation of RCC spheres which shared molecular characteristics with the spontaneous RCC spheres. Target prediction pointed out TGFβ pathway activation as a possible mechanism to drive RCC sphere formation. We demonstrate that miR-17 overexpression interferes with the TGFβ-EMT axis and hinders RCC sphere formation; and validated TGFBR2 as a direct and biologically relevant target during this process. Thus, a single miRNA may have an impact on the formation of highly tumorigenic cancer spheres of kidney cancer.
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.|Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Lichner
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Saleh
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Subramaniam
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Canada.
authors.forename: Annetta
authors.initials: A
authors.lastname: Seivwright
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.|Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Canada.
authors.forename: Gerald Joseph
authors.initials: GJ
authors.lastname: Prud'homme
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.|Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Canada.
authors.forename: George Makram
authors.initials: GM
authors.lastname: Yousef
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000473:pathology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: cancer stem cell-tumor initiating cell; clear cell renal cell carcinoma; epithelial-to-mesenchymal transition; microRNA