miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties
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Zsuzsanna Lichner1,2, Carol Saleh1, Venkateswaran Subramaniam1, Annetta Seivwright2, Gerald Joseph Prud’homme1,2, George Makram Yousef1,2
1 Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Scienceatthe Li Ka Shing Knowledge Institute
2 Department of Pathology and Laboratory Medicine, University of Toronto, M5G 1L5, Canada
George Makram Yousef, email:
Keywords: Clear cell renal cell carcinoma / microRNA / Cancer stem cell- Tumor initiating cell / Epithelial-to-mesenchymal transition
Received: January 23, 2014 Accepted: April 16, 2014 Published: April 16, 2014
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.
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