Skip to main content
Top
Published in: Tumor Biology 4/2015

01-04-2015 | Research Article

Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells

Authors: Jianlin Wang, Xisheng Yang, Bai Ruan, Bin Dai, Yuan Gao, Juanli Duan, Shibin Qu, Kaishan Tao, Kefeng Dou, Haimin Li

Published in: Tumor Biology | Issue 4/2015

Login to get access

Abstract

Due to high incidence of invasion and intrahepatic metastasis, hepatocellular carcinoma (HCC) is one of the most aggressive tumors in the world, which is also associated with the acquisition of epithelial-mesenchymal transition (EMT). Increasing evidence suggests that cancer cells with EMT traits share many biological characteristics with cancer stem cells. And miR-200a has been known as a powerful regulator of EMT. Here, we sought to investigate the role of miR-200a in regulation of EMT phenotype of liver cancer stem cells (LCSCs). We used side population (SP) sorting to obtain cancer stem-like cells from HCC cell lines and identified that the SP fraction could be enriched with LCSCs. Then, we detected the expression of miR-200a and EMT makers in SP and non-SP cells. Our results suggested that miR-200a was down-regulated in SP cells, along with relatively low epithelial marker and high mesenchymal marker. In order to find the role of miR-200a in the manipulation of EMT, we transfected miR-200a mimic into LCSCs and found that overexpression of miR-200a resulted in down-regulation of N-cadherin, ZEB2, and vimentin, but up-regulation of E-cadherin. Moreover, overexpression of miR-200a resulted in decreased migration and invasion ability in LCSCs. In conclusion, our study revealed that miR-200a played an important role in linking the characteristics of cancer stem cells with EMT phenotype in HCC, and targeting miR-200a might be an effective strategy to weaken the invasive behavior of LCSCs.
Literature
2.
go back to reference Huo TI et al. The model for end-stage liver disease-based Japan integrated scoring system may have a better predictive ability for patients with hepatocellular carcinoma undergoing locoregional therapy. Cancer. 2006;107(1):141–8.CrossRefPubMed Huo TI et al. The model for end-stage liver disease-based Japan integrated scoring system may have a better predictive ability for patients with hepatocellular carcinoma undergoing locoregional therapy. Cancer. 2006;107(1):141–8.CrossRefPubMed
3.
go back to reference Olsen SK, Brown RS, Siegel AB. Hepatocellular carcinoma: Review of current treatment with a focus on targeted molecular therapies. Therap Adv Gastroenterol. 2010;3(1):55–66.CrossRefPubMedPubMedCentral Olsen SK, Brown RS, Siegel AB. Hepatocellular carcinoma: Review of current treatment with a focus on targeted molecular therapies. Therap Adv Gastroenterol. 2010;3(1):55–66.CrossRefPubMedPubMedCentral
4.
go back to reference Chang WT et al. Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: Extending the indication for resection? Surgery. 2012;152(5):809–20.CrossRefPubMed Chang WT et al. Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: Extending the indication for resection? Surgery. 2012;152(5):809–20.CrossRefPubMed
6.
go back to reference Clarke MF et al. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–44.CrossRefPubMed Clarke MF et al. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–44.CrossRefPubMed
7.
go back to reference Dalerba P, Cho RW, Clarke MF. Cancer stem cells: Models and concepts. Annu Rev Med. 2007;58:267–84.CrossRefPubMed Dalerba P, Cho RW, Clarke MF. Cancer stem cells: Models and concepts. Annu Rev Med. 2007;58:267–84.CrossRefPubMed
8.
go back to reference Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea–a paradigm shift. Cancer Res. 2006;66(4):1883–90. discussion 1895–6.CrossRefPubMed Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea–a paradigm shift. Cancer Res. 2006;66(4):1883–90. discussion 1895–6.CrossRefPubMed
9.
go back to reference Ponti D et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506–11.CrossRefPubMed Ponti D et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506–11.CrossRefPubMed
10.
11.
go back to reference Patrawala L et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25(12):1696–708.CrossRefPubMed Patrawala L et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25(12):1696–708.CrossRefPubMed
12.
go back to reference Ricci-Vitiani L et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.CrossRefPubMed Ricci-Vitiani L et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.CrossRefPubMed
13.
go back to reference Zhang N et al. Characterization of a stem-like population in hepatocellular carcinoma MHCC97 cells. Oncol Rep. 2010;23(3):827–31.PubMed Zhang N et al. Characterization of a stem-like population in hepatocellular carcinoma MHCC97 cells. Oncol Rep. 2010;23(3):827–31.PubMed
16.
go back to reference Vazquez-Martin A et al. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle. 2010;9(18):3807–14.CrossRefPubMed Vazquez-Martin A et al. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle. 2010;9(18):3807–14.CrossRefPubMed
17.
go back to reference Goossens S et al. The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization. Blood. 2011;117(21):5620–30.CrossRefPubMed Goossens S et al. The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization. Blood. 2011;117(21):5620–30.CrossRefPubMed
18.
go back to reference Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.CrossRefPubMed Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.CrossRefPubMed
19.
go back to reference Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.CrossRefPubMed Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.CrossRefPubMed
20.
go back to reference Shin SY et al. Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res. 2010;70(17):6715–24.CrossRefPubMedPubMedCentral Shin SY et al. Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res. 2010;70(17):6715–24.CrossRefPubMedPubMedCentral
21.
go back to reference Takebe N, Warren RQ, Ivy SP. Breast cancer growth and metastasis: Interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 2011;13(3):211.CrossRefPubMedPubMedCentral Takebe N, Warren RQ, Ivy SP. Breast cancer growth and metastasis: Interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 2011;13(3):211.CrossRefPubMedPubMedCentral
22.
go back to reference Yan, H., et al., Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma. Mol Carcinog, 2013 Yan, H., et al., Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma. Mol Carcinog, 2013
24.
27.
go back to reference Xiao F et al. microRNA-200a is an independent prognostic factor of hepatocellular carcinoma and induces cell cycle arrest by targeting CDK6. Oncol Rep. 2013;30(5):2203–10.PubMed Xiao F et al. microRNA-200a is an independent prognostic factor of hepatocellular carcinoma and induces cell cycle arrest by targeting CDK6. Oncol Rep. 2013;30(5):2203–10.PubMed
28.
30.
go back to reference Bao B et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011;307(1):26–36.CrossRefPubMedPubMedCentral Bao B et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011;307(1):26–36.CrossRefPubMedPubMedCentral
31.
go back to reference Wu Q et al. MicroRNA-200a inhibits CD133/1+ ovarian cancer stem cells migration and invasion by targeting E-cadherin repressor ZEB2. Gynecol Oncol. 2011;122(1):149–54.CrossRefPubMed Wu Q et al. MicroRNA-200a inhibits CD133/1+ ovarian cancer stem cells migration and invasion by targeting E-cadherin repressor ZEB2. Gynecol Oncol. 2011;122(1):149–54.CrossRefPubMed
32.
go back to reference Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14(1):3–9.CrossRefPubMed Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14(1):3–9.CrossRefPubMed
34.
go back to reference Kang Y, Massague J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell. 2004;118(3):277–9.CrossRefPubMed Kang Y, Massague J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell. 2004;118(3):277–9.CrossRefPubMed
35.
go back to reference Yin S et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer. 2007;120(7):1444–50.CrossRefPubMed Yin S et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer. 2007;120(7):1444–50.CrossRefPubMed
36.
go back to reference Ishimoto T et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc (−) and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400.CrossRefPubMed Ishimoto T et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc (−) and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400.CrossRefPubMed
37.
go back to reference Yang W et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008;68(11):4287–95.CrossRefPubMed Yang W et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008;68(11):4287–95.CrossRefPubMed
38.
go back to reference Kimura O et al. Characterization of the epithelial cell adhesion molecule (EpCAM) + cell population in hepatocellular carcinoma cell lines. Cancer Sci. 2010;101(10):2145–55.CrossRefPubMed Kimura O et al. Characterization of the epithelial cell adhesion molecule (EpCAM) + cell population in hepatocellular carcinoma cell lines. Cancer Sci. 2010;101(10):2145–55.CrossRefPubMed
39.
go back to reference Hadnagy A et al. SP analysis may be used to identify cancer stem cell populations. Exp Cell Res. 2006;312(19):3701–10.CrossRefPubMed Hadnagy A et al. SP analysis may be used to identify cancer stem cell populations. Exp Cell Res. 2006;312(19):3701–10.CrossRefPubMed
40.
go back to reference Riekstina U et al. Embryonic stem cell marker expression pattern in human mesenchymal stem cells derived from bone marrow, adipose tissue, heart and dermis. Stem Cell Rev. 2009;5(4):378–86.CrossRefPubMed Riekstina U et al. Embryonic stem cell marker expression pattern in human mesenchymal stem cells derived from bone marrow, adipose tissue, heart and dermis. Stem Cell Rev. 2009;5(4):378–86.CrossRefPubMed
41.
go back to reference Heng JC et al. The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell. 2010;6(2):167–74.CrossRefPubMed Heng JC et al. The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell. 2010;6(2):167–74.CrossRefPubMed
42.
go back to reference Yu J et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.CrossRefPubMed Yu J et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.CrossRefPubMed
43.
go back to reference Gregory PA et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.CrossRefPubMed Gregory PA et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.CrossRefPubMed
44.
go back to reference Eades G et al. miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J Biol Chem. 2011;286(29):25992–6002.CrossRefPubMedPubMedCentral Eades G et al. miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J Biol Chem. 2011;286(29):25992–6002.CrossRefPubMedPubMedCentral
45.
go back to reference Xia H et al. miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling. J Biol Chem. 2010;285(47):36995–7004.CrossRefPubMedPubMedCentral Xia H et al. miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling. J Biol Chem. 2010;285(47):36995–7004.CrossRefPubMedPubMedCentral
46.
go back to reference Liu J et al. Downregulation of miR-200a induces EMT phenotypes and CSC-like signatures through targeting the beta-catenin pathway in hepatic oval cells. PLoS ONE. 2013;8(11):e79409.CrossRefPubMedPubMedCentral Liu J et al. Downregulation of miR-200a induces EMT phenotypes and CSC-like signatures through targeting the beta-catenin pathway in hepatic oval cells. PLoS ONE. 2013;8(11):e79409.CrossRefPubMedPubMedCentral
48.
go back to reference Kong D et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE. 2010;5(8):e12445.CrossRefPubMedPubMedCentral Kong D et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE. 2010;5(8):e12445.CrossRefPubMedPubMedCentral
49.
go back to reference Li Y et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69(16):6704–12.CrossRefPubMedPubMedCentral Li Y et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69(16):6704–12.CrossRefPubMedPubMedCentral
50.
go back to reference Tryndyak VP, Beland FA, Pogribny IP. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer. 2010;126(11):2575–83.PubMed Tryndyak VP, Beland FA, Pogribny IP. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer. 2010;126(11):2575–83.PubMed
51.
go back to reference Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.CrossRefPubMed Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.CrossRefPubMed
52.
53.
go back to reference De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.CrossRefPubMed De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.CrossRefPubMed
54.
go back to reference Heddleston JM et al. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009;8(20):3274–84.CrossRefPubMedPubMedCentral Heddleston JM et al. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009;8(20):3274–84.CrossRefPubMedPubMedCentral
Metadata
Title
Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells
Authors
Jianlin Wang
Xisheng Yang
Bai Ruan
Bin Dai
Yuan Gao
Juanli Duan
Shibin Qu
Kaishan Tao
Kefeng Dou
Haimin Li
Publication date
01-04-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2856-2

Other articles of this Issue 4/2015

Tumor Biology 4/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine