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SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1? 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-1? (HIF-1?), 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-1? expression. Mechanistic studies showed that SHARP1 interacted with HIF-1? physically, and the protein level of HIF-1? 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-1? 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.

SUBMITTER: Liao Y

PROVIDER: S-EPMC4053412 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1α level.

Liao Yun Y Lu Wen W Che Qi Q Yang Tingting T Qiu Haifeng H Zhang Huijuan H He Xiaoying X Wang Jingyun J Qiu Meiting M Zou Yingfen Y Gu Wei W Wan Xiaoping X

PloS one 20140611 6

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 ...[more]

PMID: 24918449

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Project description:We aimed to develop a novel anti-HIF-1α intrabody to decrease gemcitabine resistance in pancreatic cancer patients. Surface plasmon resonance and glutathione S-transferase pull-down assays were conducted to identify the binding affinity and specificity of anti-HIF-1α VHH212 [a single-domain antibody (nanobody)]. Molecular dynamics simulation was used to determine the protein-protein interactions between hypoxia-inducible factor-1α (HIF-1α) and VHH212. The real-time polymerase chain reaction (PCR) and Western blot analyses were performed to identify the expressions of HIF-1α and VEGF-A in pancreatic ductal adenocarcinoma cell lines. The efficiency of the VHH212 nanobody in inhibiting the HIF-1 signaling pathway was measured using a dual-luciferase reporter assay. Finally, a PANC-1 xenograft model was developed to evaluate the anti-tumor efficiency of combined treatment. Immunohistochemistry analysis was conducted to detect the expressions of HIF-1α and VEGF-A in tumor tissues. VHH212 was stably expressed in tumor cells with low cytotoxicity, high affinity, specific subcellular localization, and neutralization of HIF-1α in the cytoplasm or nucleus. The binding affinity between VHH212 and the HIF-1α PAS-B domain was 42.7 nM. Intrabody competitive inhibition of the HIF-1α heterodimer with an aryl hydrocarbon receptor nuclear translocator was used to inhibit the HIF-1/VEGF pathway in vitro. Compared with single agent gemcitabine, co-treatment with gemcitabine and a VHH212-encoding adenovirus significantly suppressed tumor growth in the xenograft model with 80.44% tumor inhibition. We developed an anti-HIF-1α nanobody and showed the function of VHH212 in a preclinical murine model of PANC-1 pancreatic cancer. The combination of VHH212 and gemcitabine significantly inhibited tumor development. These results suggested that combined use of anti-HIF-1α nanobodies with first-line treatment may in the future be an effective treatment for pancreatic cancer.

Dataset Information

SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1? level.

Publications

SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1α level.

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