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.
Highlights
Endometrial cancer (EC) is a major cause of cancer-related morbidity and mortality among women
Using Quantitative Real-time PCR (qPCR) and western blotting, we found that the SHARP1 level was elevated twofold in the EC cell line RL95-2 as compared with the Ishikawa cell line, both of which originated from adenocarcinoma of the endometrium (Figure 2A)
We evaluated the genes that encode vascular endothelial growth factor A (VEGFA, an isoform of VEGF that is crucial for tumor angiogenesis and plays a key role in endothelial cell proliferation, survival, and permeability [7,10,12,16,32]), angiopoietin-like 4 (ANGPTL4), and carbonic anhydrase 9 (CA9)
Summary
Endometrial cancer (EC) is a major cause of cancer-related morbidity and mortality among women It is the fourth most common malignancy among women in the United States, with an estimated 49,500 new cases and 8200 deaths in 2013 [1]. Angiogenesis, the formation of new blood vessels from preexisting ones, has a major role in tumor growth, progression, and metastasis [6,7]. The resulting hypoxic condition (PO2,10 mmHg [,1.5% O2]) prevents degradation of hypoxia-inducible factor-1a (HIF-1a) through VHL tumor suppressor, allowing trans-activation of pro-angiogenic factors, among which the most notable is vascular endothelial growth factor (VEGF) [8,9,10,11]. The mechanism underlying angiogenesis regulation has been extensively described in other types of cancer but only scarcely studied in EC [15]
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