title: HMGA2 functions as a competing endogenous RNA to promote lung cancer progression.
abstract: Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide. As the majority of patients present with invasive, metastatic disease, it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma, in which it contributes to cancer progression and metastasis. Here we show that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA (ceRNA) for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are also observed in vivo, where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-β co-receptor Tgfbr3 (ref. 12) as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA through differential recruitment to Argonaute 2 (Ago2), and TGF-β signalling driven by Tgfbr3 is important for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC-patient gene-expression data reveals that HMGA2 and TGFBR3 are coordinately regulated in NSCLC-patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis both as a protein-coding gene and as a non-coding RNA; such dual-function regulation of gene-expression networks reflects a novel means by which oncogenes promote disease progression.
authors.affiliation: Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Kumar
authors.affiliation: Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Armenteros-Monterroso
authors.affiliation: Bioinformatics and Biostatistics Group, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.affiliation: Bioinformatics and Biostatistics Group, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravorty
authors.affiliation: Advanced Sequencing Facility, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: Department of Genetics, Department of Pathology, the Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Monte M
authors.initials: MM
authors.lastname: Winslow
authors.affiliation: 1] Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Lung Cancer Group, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001667:Binding, Competitive / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D011509:Proteoglycans / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D059368:RNA Isoforms / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D025743:HMGA2 Protein; D035683:MicroRNAs; D011509:Proteoglycans; D059368:RNA Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C542687:mirnlet7 microRNA, mouse; C071736:betaglycan