Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer

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• 作者：Yun Liao (4) (5)
  Xiaoying He (4)
  Haifeng Qiu (5)
  Qi Che (5)
  Fangyuan Wang (5)
  Wen Lu (6)
  Zheng Chen (5)
  Meiting Qiu (4)
  Jingyun Wang (4)
  Huihui Wang (5)
  Xiaoping Wan (6)
  
  4. Department of Obstetrics and Gynecology ; International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ; Shanghai ; China
  5. Department of Obstetrics and Gynecology ; Shanghai First People鈥檚 Hospital Affiliated to Shanghai Jiao Tong University School of Medicine ; Shanghai ; China
  6. Department of Obstetrics and Gynecology ; Shanghai First Maternity and Infant Hospital Affiliated to Tong Ji University ; No. 536 ; Changle Road ; Shanghai ; 200080 ; China
  
• 关键词：Endometrial cancer ; Metastasis ; SHARP1 ; EMT ; NOTCH1
• 刊名：BMC Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：14
• 期：1
• 全文大小：2,617 KB
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  38. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/487/prepub
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

Background Mechanisms 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. Methods Human 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. Results Overexpression 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. Conclusions This 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.