title: MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells.
abstract: Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3'UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3'UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1.
authors.affiliation: the Departments of Medicine and.
authors.forename: Falguni
authors.initials: F
authors.lastname: Das
authors.affiliation: the Departments of Medicine and.
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Dey
authors.affiliation: the Departments of Medicine and.
authors.forename: Amit
authors.initials: A
authors.lastname: Bera
authors.affiliation: the Departments of Medicine and From Veterans Affairs Research and Geriatric Research.
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.affiliation: From Veterans Affairs Research and Geriatric Research, Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.affiliation: the Departments of Medicine and From Veterans Affairs Research and Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas 78229-3900 and choudhuryg@uthscsa.edu.
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000235:genetics*; D046912:Multiprotein Complexes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; D017526:Receptor, IGF Type 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt PKB; cancer; cell signaling; mTOR complex (mTORC); microRNA (miRNA)