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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

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

Authors: Yun Liao, Xiaoying He, Haifeng Qiu, Qi Che, Fangyuan Wang, Wen Lu, Zheng Chen, Meiting Qiu, Jingyun Wang, Huihui Wang, Xiaoping Wan

Published in: BMC Cancer | Issue 1/2014

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Abstract

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.
Appendix
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Literature
1.
2.
3.
Hill EK, Dizon DS: Medical therapy of endometrial cancer: current status and promising novel treatments. Drugs. 2012, 72 (5): 705-713.CrossRefPubMed
4.
Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, Gotlieb WH, Hoskins PJ, Ghatage P, Tonkin KS, Mackay HJ, Mazurka J, Sederias J, Ivy P, Dancey JE, Eisenhauer EA: Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011, 29 (24): 3278-3285.CrossRefPubMedPubMedCentral
5.
Fujimoto K, Shen M, Noshiro M, Matsubara K, Shingu S, Honda K, Yoshida E, Suardita K, Matsuda Y, Kato Y: Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins. Biochem Biophys Res Commun. 2001, 280 (1): 164-171.CrossRefPubMed
6.
Fujimoto K, Hamaguchi H, Hashiba T, Nakamura T, Kawamoto T, Sato F, Noshiro M, Bhawal UK, Suardita K, Kato Y: Transcriptional repression by the basic helix-loop-helix protein Dec2: multiple mechanisms through E-box elements. Int J Mol Med. 2007, 19 (6): 925-932.PubMed
7.
Azmi S, Taneja R: Embryonic expression of mSharp-1/mDEC2, which encodes a basic helix-loop-helix transcription factor. Mech Dev. 2002, 114 (1–2): 181-185.CrossRefPubMed
8.
Azmi S, Sun H, Ozog A, Taneja R: mSharp-1/DEC2, a basic helix-loop-helix protein functions as a transcriptional repressor of E box activity and Stra13 expression. J Biol Chem. 2003, 278 (22): 20098-20109.CrossRefPubMed
9.
Bhawal UK, Sato F, Arakawa Y, Fujimoto K, Kawamoto T, Tanimoto K, Ito Y, Sasahira T, Sakurai T, Kobayashi M, Kashima I, Kijima H, Kuniyasu H, Abiko Y, Kato Y, Sato S: Basic helix-loop-helix transcription factor DEC1 negatively regulates cyclin D1. J Pathol. 2011, 224 (3): 420-429.CrossRefPubMed
10.
Li Y, Shen Q, Kim HT, Bissonnette RP, Lamph WW, Yan B, Brown PH: The rexinoid bexarotene represses cyclin D1 transcription by inducing the DEC2 transcriptional repressor. Breast Cancer Res Treat. 2011, 128 (3): 667-677.CrossRefPubMed
11.
Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E, Basso G, Leo G, Rosato A, Bicciato S, Cordenonsi M, Piccolo S: SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature. 2012, 487 (7407): 380-384.CrossRefPubMed
12.
Yunokawa M, Tanimoto K, Nakamura H, Nagai N, Kudo Y, Kawamoto T, Kato Y, Hiyama E, Hiyama K, Nishiyama M: Differential regulation of DEC2 among hypoxia-inducible genes in endometrial carcinomas. Oncol Rep. 2007, 17 (4): 871-878.PubMed
13.
Liao Y, Lu W, Che Q, Yang T, Qiu H, Zhang H, He X, Wang J, Qiu M, Zou Y, Gu W, Wan X: SHARP1 Suppresses Angiogenesis of Endometrial Cancer by Decreasing Hypoxia-Inducible Factor-1alpha Level. PLoS One. 2014, 9 (6): e99907-CrossRefPubMedPubMedCentral
14.
Yang J, Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008, 14 (6): 818-829.CrossRefPubMed
15.
Lee JM, Dedhar S, Kalluri R, Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006, 172 (7): 973-981.CrossRefPubMedPubMedCentral
16.
Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U: Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A. 2008, 105 (17): 6392-6397.CrossRefPubMedPubMedCentral
17.
Zhu YM, Zhao WL, Fu JF, Shi JY, Pan Q, Hu J, Gao XD, Chen B, Li JM, Xiong SM, Gu LJ, Tang JY, Liang H, Jiang H, Xue YQ, Shen ZX, Chen Z, Chen SJ: NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clin Cancer Res. 2006, 12 (10): 3043-3049.CrossRefPubMed
18.
Reedijk M, Pinnaduwage D, Dickson BC, Mulligan AM, Zhang H, Bull SB, O'Malley FP, Egan SE, Andrulis IL: JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Res Treat. 2008, 111 (3): 439-448.CrossRefPubMed
19.
Shi TP, Xu H, Wei JF, Ai X, Ma X, Wang BJ, Ju ZH, Zhang GX, Wang C, Wu ZQ, Zhang X: Association of low expression of notch-1 and jagged-1 in human papillary bladder cancer and shorter survival. J Urol. 2008, 180 (1): 361-366.CrossRefPubMed
20.
Mitsuhashi Y, Horiuchi A, Miyamoto T, Kashima H, Suzuki A, Shiozawa T: Prognostic significance of Notch signalling molecules and their involvement in the invasiveness of endometrial carcinoma cells. Histopathology. 2012, 60 (5): 826-837.CrossRefPubMed
21.
Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH: Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009, 69 (6): 2400-2407.CrossRefPubMedPubMedCentral
22.
Bao B, Wang Z, Ali S, Kong D, Li Y, Ahmad A, Banerjee S, Azmi AS, Miele L, Sarkar FH: Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011, 307 (1): 26-36.CrossRefPubMedPubMedCentral
23.
24.
Creasman W: Revised FIGO staging for carcinoma of the endometrium. Int J Gynaecol Obstet. 2009, 105 (2): 109-CrossRefPubMed
25.
Remmele W, Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987, 8 (3): 138-140.PubMed
26.
Yang T, Qiu H, Bao W, Li B, Lu C, Du G, Luo X, Wang L, Wan X: Epigenetic inactivation of EFEMP1 is associated with tumor suppressive function in endometrial carcinoma. PLoS One. 2013, 8 (6): e67458-CrossRefPubMedPubMedCentral
27.
Bao W, Qiu H, Yang T, Luo X, Zhang H, Wan X: Upregulation of TrkB Promotes Epithelial-Mesenchymal Transition and Anoikis Resistance in Endometrial Carcinoma. PLoS One. 2013, 8 (7): e70616-CrossRefPubMedPubMedCentral
28.
Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, Aranda S, Palomo S, McCormick F, Izpisúa-Belmonte JC, de la Pompa JL: Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004, 18 (1): 99-115.CrossRefPubMedPubMedCentral
29.
Wang Z, Li Y, Kong D, Sarkar FH: The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr Drug Targets. 2010, 11 (6): 745-751.CrossRefPubMedPubMedCentral
30.
Liu Y, Sato F, Kawamoto T, Fujimoto K, Morohashi S, Akasaka H, Kondo J, Wu Y, Noshiro M, Kato Y, Kijima H: Anti-apoptotic effect of the basic helix-loop-helix (bHLH) transcription factor DEC2 in human breast cancer cells. Genes Cells. 2010, 15 (4): 315-325.CrossRefPubMed
31.
Wu Y, Sato F, Bhawal UK, Kawamoto T, Fujimoto K, Noshiro M, Seino H, Morohashi S, Kato Y, Kijima H: BHLH transcription factor DEC2 regulates pro-apoptotic factor Bim in human oral cancer HSC-3 cells. Biomed Res. 2012, 33 (2): 75-82.CrossRefPubMed
32.
Gulbagci NT, Li L, Ling B, Gopinadhan S, Walsh M, Rossner M, Nave KA, Taneja R: SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP. EMBO Rep. 2009, 10 (1): 79-86.CrossRefPubMed
33.
Rossner MJ, Oster H, Wichert SP, Reinecke L, Wehr MC, Reinecke J, Eichele G, Taneja R, Nave KA: Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice. PLoS One. 2008, 3 (7): e2762-CrossRefPubMedPubMedCentral
34.
Sato F, Bhawal UK, Kawamoto T, Fujimoto K, Imaizumi T, Imanaka T, Kondo J, Koyanagi S, Noshiro M, Yoshida H, Kusumi T, Kato Y, Kijima H: Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression. Genes Cells. 2008, 13 (2): 131-144.CrossRefPubMed
35.
Hamaguchi H, Fujimoto K, Kawamoto T, Noshiro M, Maemura K, Takeda N, Nagai R, Furukawa M, Honma S, Honma K, Kurihara H, Kato Y: Expression of the gene for Dec2, a basic helix-loop-helix transcription factor, is regulated by a molecular clock system. Biochem J. 2004, 382 (Pt 1): 43-50.CrossRefPubMedPubMedCentral
36.
Zhang J, Wei J, Lu J, Tong Z, Liao B, Yu B, Zheng F, Huang X, Chen Z, Fang Y, Li B, Chen W, Xie D, Luo J: Overexpression of Rab25 contributes to metastasis of bladder cancer through induction of epithelial-mesenchymal transition and activation of Akt/GSK-3beta/Snail signaling. Carcinogenesis. 2013, 34 (10): 2401-2408.CrossRefPubMed
37.
Tanaka Y, Terai Y, Kawaguchi H, Fujiwara S, Yoo S, Tsunetoh S, Takai M, Kanemura M, Tanabe A, Ohmichi M: Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancer. Cancer Biol Ther. 2013, 14 (1): 13-19.CrossRefPubMedPubMedCentral
Metadata
Title
Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer
Authors
Yun Liao
Xiaoying He
Haifeng Qiu
Qi Che
Fangyuan Wang
Wen Lu
Zheng Chen
Meiting Qiu
Jingyun Wang
Huihui Wang
Xiaoping Wan
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-487

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