Abstract
BackgroundMechanisms governing the metastasis of endometrial cancer (EC) are poorly defined. Recent data support a role for Enhancer-of-split and hairy-related protein 1 (SHARP1), a basic helix-loop-helix transcription repressor, in regulating invasiveness and angiogenesis of several human cancers. However, the role of SHARP1 in metastasis of EC remains unclear.MethodsHuman EC cell lines (Ishikawa and HEC-1B) were used. SHARP1 was upregulated by lentivirus transduction, while intracellular domain of NOTCH1 (ICN) were upregulated by transient transfection with plasmids. Effects of SHARP1 on cell migration and invasion were evaluated by wound healing assay and transwell invasion assay. Experimental metastasis assay were performed in nude mice. Effects of SHAPR1 on protein levels of target genes were detected by western blotting. Furthermore, the association between SHARP1 and the NOTCH1/EMT pathway was further verified in EC tissue specimens by immunohistochemical analysis.ResultsOverexpression of SHARP1 in EC cells inhibited cell migration, invasion, and metastasis. Exogenous SHARP1 overexpression affected the proteins levels of genes involved in EMT process and NOTCH1 signaling pathway. Upregulation of ICN in SHARP1-overexpressing Ishikawa cells induced cell migration and an EMT phenotype. Additionally, immunohistochemical analysis demonstrated that SHARP1 protein levels were lower in metastatic EC than in primary tumors, and statistical analysis revealed correlations between levels of SHARP1 and markers of EMT and NOTCH1 signaling pathway in human EC tissue specimen.ConclusionsThis work supports a role for SHARP1 in suppressing EMT and metastasis in EC by attenuating NOTCH1 signaling. Therefore, SHARP1 may be a novel marker for lymphatic metastasis in EC patients.
Highlights
Mechanisms governing the metastasis of endometrial cancer (EC) are poorly defined
Wound-healing and transwell invasion assays both demonstrated that the migration and invasion capabilities of Ishikawa and HEC-1B cells were significantly suppressed by split and hairy-related protein 1 (SHARP1) overexpression (Figure 1B and C)
Invasive EC cells primarily metastasize to the lymphatic system, and we showed that SHARP1 overexpression decreased lymph-node metastases compared with primary tumors
Summary
Recent data support a role for Enhancer-of-split and hairy-related protein 1 (SHARP1), a basic helix-loop-helix transcription repressor, in regulating invasiveness and angiogenesis of several human cancers. Low-level expression of SHARP1 is associated with the tumor stage in EC [12], and SHARP1 suppresses breast cancer metastasis by degrading hypoxia-inducible factor 1α (HIF-1α) [11]. We found that SHARP1 suppresses angiogenesis of endometrial cancer [13]. It remains unknown whether SHARP1 contributes to EC metastasis
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