title: Epigenetic silencing of miR-130a ameliorates hemangioma by targeting tissue factor pathway inhibitor 2 through FAK/PI3K/Rac1/mdm2 signaling.
abstract: Hemangiomas are the most common vascular tumors that occur frequently in prematures and females. microRNA (miR)-130a is associated with the growth and invasion in many tumors, and its role in hemangiomas has not been addressed so far. The present study revealed that miR‑130a was overexpressed in infantile hemangioma tissues compared with matched tumor-adjacent tissues. The inhibitor of miR-130a restrained cell growth and induced cell apoptosis in vitro. miR‑130a inhibitor also induced a cell cycle arrest at G2/M phase. Further studies revealed that tissue factor pathway inhibitor 2 (TFPI2) was a novel miR-130a target, due to miR-130a bound directly to its 3'-untranslated region and miR-130a inhibitor enhanced the expression of TFPI2. Contrary to the effects of miR-130a inhibitor, TFPI2 siRNA strongly promoted cell growth and colony formation, whereas TFPI2 overexpression contributed to the suppressing effect of miR-130a inhibitor in cell viability. Furthermore, miR-130a inhibitor reduced the activation of focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/Rac1/anti-mouse double minute (mdm2) pathway proteins, inhibited the expression and nuclear translocation of mdm2. Moreover, FAK overexpression prevented miR-130a inhibitor-induced cell cycle arrest and decrease of cell viability. In vivo experiments, miR-130a inhibition effectively suppressed the tumor growth, restrained angiogenesis by decreasing the expression of angiogenesis markers and the percentage of CD31+ and CD34+. Taken together, our research indicated that miR-130a functions as an oncogene by targeting TFPI2, miR-130a inhibition reduced the growth and angiogenesis of hemangioma by inactivating the FAK/PI3K/Rac1/mdm2 pathway. Thus, miR-130a may serve as a potential therapeutic strategy for the treatment of hemangioma.
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Fa-Gang
authors.initials: FG
authors.lastname: Wang
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Ren-Rong
authors.initials: RR
authors.lastname: Liu
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Guang-Qi
authors.initials: GQ
authors.lastname: Xu
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Jian-Hai
authors.initials: JH
authors.lastname: Bi
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: Huo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D053492:Elafin / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006391:Hemangioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D053492:Elafin; D006023:Glycoproteins; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; C506806:PI3 protein, human; C107953:RAC1 protein, human; C021240:tissue-factor-pathway inhibitor 2; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020830:rac1 GTP-Binding Protein