title: A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression.
abstract: Ovarian cancer is the leading cause of death of all gynecologic tumors, associated with widespread peritoneal dissemination and malignant ascites. Key to this is the ability to form multicellular spheroids (MCS); however, the tumor-specific factors that regulate MCS formation are unclear. p70 S6 kinase (p70S6K), which is a downstream effector of phosphatidylinositol 3-kinase/Akt, is frequently constitutively active in ovarian carcinoma. Here we identify p70S6K as a vital regulator of MCS formation. We also uncover a new mechanism of p70S6K function as a component of the microRNA biogenesis machinery in this process. We show that p70S6K phosphorylates, and inhibits the interaction of tristetraprolin (TTP) and Dicer that promotes the expression of a subset of miRNAs, including the maturation of miR-145. Twist and Sox9 are two divergent targets of miR-145, thereby enhancing N-cadherin, but not other cadherin, expression and MCS formation. Activating miR-145 suppresses ovarian tumor growth and metastasis in an orthotopic xenograft mouse model. Meta-analysis in the Oncomine database reveals that high p70S6K and low TTP levels are associated with ovarian tumor progression. These results define a critical link between p70S6K, miRNA maturation, and MCS formation that may underlie poor clinical outcome of ovarian cancer patients for developing novel therapeutic strategies.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong.
authors.forename: Sophia So Ngo
authors.initials: SS
authors.lastname: Lam
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong.
authors.forename: Carman Ka Man
authors.initials: CK
authors.lastname: Ip
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong.
authors.forename: Abby Sin Chi
authors.initials: AS
authors.lastname: Mak
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong.
authors.forename: Alice Sze Tsai
authors.initials: AS
authors.lastname: Wong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: microRNA biogenesis; multicellular spheroid formation; ovarian cancer; p70 S6 kinase