title: Apurinic/apyrimidinic endonuclease 1 regulates angiogenesis in a transforming growth factor β-dependent manner in human osteosarcoma.
abstract: Angiogenesis plays an important role in tumor growth and metastasis and has been reported to be inversely correlated with overall survival of osteosarcoma patients. It has been shown that apurinic/apyrimidinic endonuclease 1 (APE1), a dually functional protein possessing both base excision repair and redox activities, is involved in tumor angiogenesis, although these mechanisms are not fully understood. Our previous study showed that the expression of transforming growth factor β (TGFβ) was significantly reduced in APE1-deficient osteosarcoma cells. Transforming growth factor β promotes cancer metastasis through various mechanisms including immunosuppression, angiogenesis, and invasion. In the current study, we initially revealed that APE1, TGFβ, and microvessel density (MVD) have pairwise correlation in osteosarcoma tissue samples, whereas TGFβ, tumor size, and MVD were inversely related to the prognosis of the cohort. We found that knocking down APE1 in osteosarcoma cells resulted in TGFβ downregulation. In addition, APE1-siRNA led to suppression of angiogenesis in vitro based on HUVECs in Transwell and Matrigel tube formation assays. Reduced secretory protein level of TGFβ of culture medium also resulted in decreased phosphorylation of Smad3 of HUVECs. In a mouse xenograft model, siRNA-mediated silencing of APE1 downregulated TGFβ expression, tumor size, and MVD. Collectively, the current evidence indicates that APE1 regulates angiogenesis in osteosarcoma by controlling the TGFβ pathway, suggesting a novel target for anti-angiogenesis therapy in human osteosarcoma.
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Shan
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Dai
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qing
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Shiheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Chongyi
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Jiangdong
authors.initials: J
authors.lastname: Sui
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000098:blood supply* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology*; D012516:Osteosarcoma / Q000098:blood supply* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: Angiogenesis; apurinic/apyrimidinic endonuclease 1 (APE1); osteosarcoma; redox; transforming growth factor β (TGFβ)