title: miR‑221 targets HMGA2 to inhibit bleomycin‑induced pulmonary fibrosis by regulating TGF‑β1/Smad3-induced EMT.
abstract: MicroRNA (miR)-221 plays an essential role in the epithelial-mesenchymal transition (EMT). High mobility group AT-hook 2 (HMGA2), is a key regulator of EMT. However, the role of miR‑221 in pulmonary fibrosis, and the association between miR‑221 and HMGA2 remain largely unknown. For this purpose, we examined the expression of miR‑221 and HMGA2 in human idiopathic pulmonary fibrosis (IPF) tissues and pulmonary cells, namely the adenocarcinoma A549 and human bronchial epithelium (HBE) cell lines, and found that the expression of miR‑221 was inhibited in both tissues and cells whereas high mRNA and protein expression of HMGA2 was observed. Additionally, transforming growth factor‑β1 (TGF‑β1) induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely N‑cadherin, vimentin, α‑smooth muscle actin, collagen I and collagen III, and the downregulated expression of the epithelial marker E-cadherin in A549 and HBE cells. We then performed transfection with miR‑221 mimics, and found that the expression of phosphorylated-Smad3 in miR‑221‑overexpressing cells was significantly downregulated, compared with that in the TGF‑β1-treated cells without transfection. Furthermore, the overexpression of miR‑221 decreased the expression of HMGA2, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. HMGA2 was directly targeted by miR‑221 which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin (BLM)‑induced pulmonary fibrosis was used to confirm the effect of miR‑221 on EMT. Hematoxylin and eosin staining showed that BLM induced thicker alveolar walls and more collagen deposition, whereas miR‑221 treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following miR‑221 injection. Taken together, these findings sugest that miR‑221 targets HMGA2 to inhibit BLM‑induced pulmonary fibrosis through the TGF‑β1/Smad3 signaling pathway.
authors: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors: Yi-Chun
authors: YC
authors: Wang
authors: Department of Critical Care Medicine, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Jing-Shi
authors: JS
authors: Liu
authors: Department of Hospice and Palliative Care, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Hao-Ke
authors: HK
authors: Tang
authors: Department of Critical Care Medicine, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Jing
authors: J
authors: Nie
authors: Department of Critical Care Medicine, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Ji-Xian
authors: JX
authors: Zhu
authors: Department of Critical Care Medicine, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Ling-Ling
authors: LL
authors: Wen
authors: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors: Qu-Lian
authors: QL
authors: Guo
mesh_terms: D000072283:A549 Cells; D000818:Animals; D001761:Bleomycin; D001980:Bronchi / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D001761:Bleomycin; D025743:HMGA2 Protein; D035683:MicroRNAs; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C525709:MIR221, human; C546122:MIRN221 microRNA, mouse