title: Rapamycin inhibits the proliferation of endothelial cells in hemangioma by blocking the mTOR-FABP4 pathway.
abstract: FABP4 is widely expressed in both normal and pathologic tissues. It promotes cell proliferation, survival and migration of endothelial cells, and therefore, angiogenesis. However, the role of FABP4 in hemangioma or hemangioma endothelial cells (HemECs) has not been explored. In this study, we investigated whether FABP4 directly regulates the proliferation of HemECs. The expression of cell cycle checkpoint genes was analyzed with the microarray data of human dermal microvascular endothelial cells (HDVECs) and infantile hemangioma endothelial cells. Real-time RT-PCR and western blotting were used to examine the expression of FABP4 in HemECs. Next, the FABP4 expression was inhibited in HemECs using siRNA or rapamycin and upregulated using retroviral transduction of HemECs to assess its influence on proliferation of HemECs. The microarray data showed that cell cycle checkpoint genes were upregulated in HemECs. Moreover, HemECs showed significantly higher proliferation rates than HDVECs. The expression of FABP4 and mTOR was increased in the HemECs. While FABP4 knockdown reduced the BrdU incorporation and cell number of HemECs as expected, cell proliferation was accelerated by FABP4 over-expression. Moreover, rapamycin (10nM) inhibited mTOR-FABP4 signaling and HemEC proliferation. Taken together, these results indicated that mTOR signaling pathway-activated FABP4 directly regulates the proliferation of endothelial cells in hemangioma. Rapamycin and inhibitors of FABP4 have therapeutic potential for treating infantile hemangiomas.
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, No. 355, Luding Road, Shanghai 200062, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, No. 355, Luding Road, Shanghai 200062, People's Republic of China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Radiology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People's Republic of China.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, No. 355, Luding Road, Shanghai 200062, People's Republic of China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, No. 355, Luding Road, Shanghai 200062, People's Republic of China. Electronic address: chhshent@126.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018324:Hemangioma, Capillary / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Endothelial cells; FABP4; Hemangioma; Rapamycin; mTOR