title: SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1α level.
abstract: Recent data support a role for SHARP1, a basic helix-loop-helix transcription repressor, in the regulation of malignant cell behavior in several human cancers. However, the expression and role of SHARP1 during the development of endometrial cancer (EC) remain unclear. Here we show that upregulation of SHARP1 suppressed tumor angiogenesis by decreasing hypoxia-inducible factor-1α (HIF-1α), inhibited cell viability and tumor growth in EC. Immunohistochemical staining showed that the expression of SHARP1 was negatively correlated with tumor stage, histological grade, myometrial invasion, lymph node metastasis, blood vessel permeation in the myometrium and HIF-1α expression. Mechanistic studies showed that SHARP1 interacted with HIF-1α physically, and the protein level of HIF-1α and the mRNA level of its target genes (VEGFA, ANGPTL4 and CA9) were decreased by SHARP1 under hypoxia. Upregulation of SHARP1 in EC impeded hypoxia-induced angiogenesis by reducing VEGF secretion. Immunohistochemical analysis verified a correlation between decreased SHARP1 expression and increased microvessel density in EC tissues. Additionally, SHARP1 inhibited cell viability in EC cell lines. Overexpression of SHARP1 in vivo inhibited tumor growth and angiogenesis, and decreased HIF-1α expression. In this study, we established SHARP1 as a novel tumor suppressor of EC and shed light on the mechanisms by how SHARP1 inhibited EC progression. Therefore, SHARP1 may be a valuable prognostic biomarker for EC progression and shows promise as a new potential target for antiangiogenic therapeutics in human EC.
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Che
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Departments of Pathology and Biobank, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Meiting
authors.initials: M
authors.lastname: Qiu
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingfen
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
mesh_terms: D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002199:Capillary Permeability / Q000235:genetics; D016022:Case-Control Studies; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D009215:Myometrium / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C422085:BHLHE41 protein, human; C497442:HIF1A protein, human; C467484:VEGFA protein, human