title: Let-7a suppresses glioma cell proliferation and invasion through TGF-β/Smad3 signaling pathway by targeting HMGA2.
abstract: It has been shown that let-7a was associated with the tumorigenesis of glioma. Our study was designed to infer how let-7a targets high-mobility AT-hook 2 (HMGA2) and suppresses glioma cell proliferation, invasion, and migration. Glioma tissues from 60 glioma patients and 10 normal brain tissues were collected in this study. Real-time quantitative reverse transcription-PCR (qRT-PCR) and in situ hybridization were used to detect the expression levels of let-7a in tissues and cells. The HMGA2 and the proteins related to transforming growth factor-beta (TGF-β)/Smad3 signaling pathway were measured by immunohistochemistry and western blot. Glioma U87 cells were transfected with either let-7a mimics, HMGA2 small interfering RNA (siRNA), let-7a mimics + HMGA2, HMGA2, or scramble. A cell counting kit-8 (CCK-8) assay was used to detect and compare the difference among various transfection groups. Glioma tumor xenograft models on mice were built to evaluate the effects of let-7a and HMGA2 siRNA on glioma tumors in vivo. The expression level of let-7a significantly downregulated in glioma tissues, while the HMGA2 positive expression rate notably increased compared with those in normal brain tissues (all P < 0.05). Moreover, the expression levels of let-7a and HMGA2 were correlated with glioma grades (all P < 0.05). The proliferation of U87 cells transfected with let-7a mimics or HMGA2 siRNA was significantly inhibited in comparison to the blank control group and the apoptosis rates of U87 cells transfected with let-7a mimics or HMGA2 siRNA were significantly higher than those in the blank control group (all P < 0.05). Let-7a or HMGA2 siRNA could remarkably attenuate the invasion and migration ability of glioma cells (all P < 0.05). Apart from that, over-expressed exogenous HMGA2 could reverse the inhibition of glioma cell metastasis and proliferation induced by let-7a. As suggested by immunohistochemistry and western blot, the expression levels of TGF-β1 and p-Smad3 significantly decreased compared with the blank or scramble group (all P < 0.05). Thus, let-7a and HMGA2 siRNA could effectively suppress the growth of tumors in glioma xenograft models. Let-7a may suppress the proliferation and invasion of glioma cells through mediating TGF-β/Smad3 signaling pathway by targeting HMGA2.
authors.affiliation: Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Xinmin Street 71, Changchun, 130021, Jilin Province, China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Xinmin Street 71, Changchun, 130021, Jilin Province, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Xinmin Street 71, Changchun, 130021, Jilin Province, China. 995541001@qq.com.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Ma
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; D035683:MicroRNAs; D012333:RNA, Messenger; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C487931:mirnlet7 microRNA, human
keywords: Glioma; HMGA2; Invasion; Let-7a; Migration; TGF-β; Xenograft model