title: MiR-99a Inhibits Cell Proliferation and Tumorigenesis through Targeting mTOR in Human Anaplastic Thyroid Cancer.
abstract: MicroRNAs (miRNAs) are emerging as critical regulators in carcinogenesis and tumor progression. Recently, miR-99a has been reported as a tumor suppressor gene in various human cancers, but its functions in the context of anaplastic thyroid cancer (ATC) remain unknown. In this study, we reported that miR-99a was commonly downregulated in ATC tissue specimens and cell lines with important functional consequences. Overexpression of miR-99a not only dramatically reduced ATC cell viability by inducing cell apoptosis and accumulation of cells at G1 phase, but also inhibited tumorigenicity in vivo. We then screened and identified a novel miR-99a target, mammalian target of rapamycin (mTOR), and it was further confirmed by luciferase assay. Up-regulation of miR-99a would markedly reduce the expression of mTOR and its downstream phosphorylated proteins (p-4E- BP1 and p-S6K1). Similar to restoring miR-99a expression, mTOR down-regulation suppressed cell viability and increased cell apoptosis, whereas restoration of mTOR expression significantly reversed the miR-99a antitumor activity and the inhibition of mTOR/p-4E-BP1/p-S6K1 signal pathway profile. In clinical specimens and cell lines, mTOR was commonly overexpressed and its protein levels were statistically inversely correlated with miR-99a expression. Taken together, our results demonstrated for the first time that miR-99a functions as a tumor suppressor and plays an important role in inhibiting the tumorigenesis through targeting the mTOR/p- 4E-BP1/p-S6K1 pathway in ATC cells. Given these, miR-99a may serve as a novel prognostic/diagnostic and therapeutic target for treating ATC.
authors.affiliation: Department of Anaesthesiology, Yongchuan Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China E-mail : jianbin198028262@sina.com.
authors.forename: Hou-Gang
authors.initials: HG
authors.lastname: Huang
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.forename: Shuai
authors.initials: S
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Jian
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1