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Published in: Cellular Oncology 4/2018

01-08-2018 | Original Paper

Identification of biomarkers associated with partial epithelial to mesenchymal transition in the secretome of slug over-expressing hepatocellular carcinoma cells

Authors: Oğuzhan Karaosmanoğlu, Sreeparna Banerjee, Hülya Sivas

Published in: Cellular Oncology | Issue 4/2018

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Abstract

Background

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Complete epithelial to mesenchymal transition (EMT) has long been considered as a crucial step for metastasis initiation. It has, however, become apparent that many carcinoma cells can metastasize without complete loss of epithelial traits or with incomplete gain of mesenchymal traits, i.e., partial EMT. Here, we aimed to determine the similarities and differences between complete and partial EMT through over-expression of the EMT-associated transcription factor Slug in different HCC-derived cell lines.

Methods

Slug over-expressing HCC-derived HepG2 and Huh7 cells were assessed for their EMT, chemo-resistance and stemness features using Western blotting, qRT-PCR, neutral red uptake, doxorubicin accumulation and scratch wound healing assays. We also collected conditioned media from Slug over-expressing HCC cells and analyzed its exosomal protein content for the presence of chemo-resistance and partial EMT markers using MALDI-TOF/TOF and ELISA assays, respectively.

Results

We found that Slug over-expression resulted in the induction of both complete and partial EMT in the different HCC-derived cell lines tested. Complete EMT was characterized by downregulation of E-cadherin and upregulation of ZEB2. Partial EMT was characterized by upregulation of E-cadherin and downregulation of vimentin and ZEB2. Interestingly, we found that Slug induced chemo-resistance through downregulation of the ATP binding cassette (ABC) transporter ABCB1 and upregulation of the ABC transporter ABCG2, as well as through expression of CD133, a stemness marker that exhibited a similar expression pattern in cells with either a complete or a partial EMT phenotype. In addition, we found that Slug-mediated partial EMT was associated with enhanced exosomal secretion of post-translationally modified fibronectin 1 (FN1), collagen type II alpha 1 (COL2A1) and native fibrinogen gamma chain (FGG).

Conclusions

From our data we conclude that the exosomal proteins identified may be considered as potential non-invasive biomarkers for chemo-resistance and partial EMT in HCC.
Literature
1.
go back to reference A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward, D. Forman, Global cancer statistics. CA Cancer J Clin 61, 69–90 (2011)CrossRefPubMed A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward, D. Forman, Global cancer statistics. CA Cancer J Clin 61, 69–90 (2011)CrossRefPubMed
3.
go back to reference T.R. Samatov, A.G. Tonevitsky, U. Schumacher, Epithelial-mesenchymal transition: Focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. Mol Cancer 12, 107 (2013)CrossRefPubMedPubMedCentral T.R. Samatov, A.G. Tonevitsky, U. Schumacher, Epithelial-mesenchymal transition: Focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. Mol Cancer 12, 107 (2013)CrossRefPubMedPubMedCentral
4.
go back to reference S. Bugide, V.K. Gonugunta, V. Penugurti, V.L. Malisetty, R.K. Vadlamudi, B. Manavathi, HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol 40, 133–144 (2017)CrossRef S. Bugide, V.K. Gonugunta, V. Penugurti, V.L. Malisetty, R.K. Vadlamudi, B. Manavathi, HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol 40, 133–144 (2017)CrossRef
5.
go back to reference H. Peinado, F. Marin, E. Cubillo, H.J. Stark, N. Fusenig, M.A. Nieto, A. Cano, Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117, 2827–2839 (2004)CrossRefPubMed H. Peinado, F. Marin, E. Cubillo, H.J. Stark, N. Fusenig, M.A. Nieto, A. Cano, Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117, 2827–2839 (2004)CrossRefPubMed
6.
go back to reference P. Savagner, D.F. Kusewitt, E.A. Carver, F. Magnino, C. Choi, T. Gridley, L.G. Hudson, Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202, 858–866 (2005)CrossRefPubMed P. Savagner, D.F. Kusewitt, E.A. Carver, F. Magnino, C. Choi, T. Gridley, L.G. Hudson, Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202, 858–866 (2005)CrossRefPubMed
7.
go back to reference V. Bolos, H. Peinado, M.A. Perez-Moreno, M.F. Fraga, M. Esteller, A. Cano, The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: A comparison with snail and E47 repressors. J Cell Sci 116, 499–511 (2003)CrossRefPubMed V. Bolos, H. Peinado, M.A. Perez-Moreno, M.F. Fraga, M. Esteller, A. Cano, The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: A comparison with snail and E47 repressors. J Cell Sci 116, 499–511 (2003)CrossRefPubMed
8.
go back to reference X.L. Zhao, B.C. Sun, D. Sun, T.J. Liu, N. Che, Q. Gu, X.Y. Dong, R. Li, Y.R. Liu, J. Li, Slug promotes hepatocellular cancer cell progression by increasing sox2 and nanog expression. Oncol Rep 33, 149–156 (2015)CrossRefPubMed X.L. Zhao, B.C. Sun, D. Sun, T.J. Liu, N. Che, Q. Gu, X.Y. Dong, R. Li, Y.R. Liu, J. Li, Slug promotes hepatocellular cancer cell progression by increasing sox2 and nanog expression. Oncol Rep 33, 149–156 (2015)CrossRefPubMed
9.
go back to reference Y. Sun, G.D. Song, N. Sun, J.Q. Chen, S.S. Yang, Slug overexpression induces stemness and promotes hepatocellular carcinoma cell invasion and metastasis. Oncol Lett 7, 1936–1940 (2014)CrossRefPubMedPubMedCentral Y. Sun, G.D. Song, N. Sun, J.Q. Chen, S.S. Yang, Slug overexpression induces stemness and promotes hepatocellular carcinoma cell invasion and metastasis. Oncol Lett 7, 1936–1940 (2014)CrossRefPubMedPubMedCentral
10.
go back to reference M. Zheng, Y.P. Jiang, W. Chen, K.D. Li, X. Liu, S.Y. Gao, H. Feng, S.S. Wang, J. Jiang, X.R. Ma, X. Cen, Y.J. Tang, Y. Chen, Y.F. Lin, Y.L. Tang, X.H. Liang, Snail and slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma. Oncotarget 6, 6794–6810 (2015)PubMedCentral M. Zheng, Y.P. Jiang, W. Chen, K.D. Li, X. Liu, S.Y. Gao, H. Feng, S.S. Wang, J. Jiang, X.R. Ma, X. Cen, Y.J. Tang, Y. Chen, Y.F. Lin, Y.L. Tang, X.H. Liang, Snail and slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma. Oncotarget 6, 6794–6810 (2015)PubMedCentral
11.
go back to reference P. Leroy, K.E. Mostov, Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Mol Biol Cell 18, 1943–1952 (2007)CrossRefPubMedPubMedCentral P. Leroy, K.E. Mostov, Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Mol Biol Cell 18, 1943–1952 (2007)CrossRefPubMedPubMedCentral
12.
go back to reference J.J. Christiansen, A.K. Rajasekaran, Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66, 8319–8326 (2006)CrossRefPubMed J.J. Christiansen, A.K. Rajasekaran, Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66, 8319–8326 (2006)CrossRefPubMed
13.
go back to reference M. Yu, A. Bardia, B.S. Wittner, S.L. Stott, M.E. Smas, D.T. Ting, S.J. Isakoff, J.C. Ciciliano, M.N. Wells, A.M. Shah, K.F. Concannon, M.C. Donaldson, L.V. Sequist, E. Brachtel, D. Sgroi, J. Baselga, S. Ramaswamy, M. Toner, D.A. Haber, S. Maheswaran, Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013)CrossRefPubMedPubMedCentral M. Yu, A. Bardia, B.S. Wittner, S.L. Stott, M.E. Smas, D.T. Ting, S.J. Isakoff, J.C. Ciciliano, M.N. Wells, A.M. Shah, K.F. Concannon, M.C. Donaldson, L.V. Sequist, E. Brachtel, D. Sgroi, J. Baselga, S. Ramaswamy, M. Toner, D.A. Haber, S. Maheswaran, Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013)CrossRefPubMedPubMedCentral
14.
go back to reference L. Lobastova, D. Kraus, A. Glassmann, D. Khan, C. Steinhauser, C. Wolff, N. Veit, J. Winter, R. Probstmeier, Collective cell migration of thyroid carcinoma cells: A beneficial ability to override unfavourable substrates. Cell Oncol 40, 63–76 (2017)CrossRef L. Lobastova, D. Kraus, A. Glassmann, D. Khan, C. Steinhauser, C. Wolff, N. Veit, J. Winter, R. Probstmeier, Collective cell migration of thyroid carcinoma cells: A beneficial ability to override unfavourable substrates. Cell Oncol 40, 63–76 (2017)CrossRef
15.
go back to reference A. Lecharpentier, P. Vielh, P. Perez-Moreno, D. Planchard, J.C. Soria, F. Farace, Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer 105, 1338–1341 (2011)CrossRefPubMedPubMedCentral A. Lecharpentier, P. Vielh, P. Perez-Moreno, D. Planchard, J.C. Soria, F. Farace, Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer 105, 1338–1341 (2011)CrossRefPubMedPubMedCentral
16.
go back to reference R. Paduch, The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol 39, 397–410 (2016)CrossRef R. Paduch, The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol 39, 397–410 (2016)CrossRef
17.
go back to reference N. Aceto, A. Bardia, D.T. Miyamoto, M.C. Donaldson, B.S. Wittner, J.A. Spencer, M. Yu, A. Pely, A. Engstrom, H. Zhu, B.W. Brannigan, R. Kapur, S.L. Stott, T. Shioda, S. Ramaswamy, D.T. Ting, C.P. Lin, M. Toner, D.A. Haber, S. Maheswaran, Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014)CrossRefPubMedPubMedCentral N. Aceto, A. Bardia, D.T. Miyamoto, M.C. Donaldson, B.S. Wittner, J.A. Spencer, M. Yu, A. Pely, A. Engstrom, H. Zhu, B.W. Brannigan, R. Kapur, S.L. Stott, T. Shioda, S. Ramaswamy, D.T. Ting, C.P. Lin, M. Toner, D.A. Haber, S. Maheswaran, Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014)CrossRefPubMedPubMedCentral
18.
go back to reference A. Grosse-Wilde, A. Fouquier d'Herouel, E. McIntosh, G. Ertaylan, A. Skupin, R.E. Kuestner, A. del Sol, K.A. Walters, S. Huang, Stemness of the hybrid epithelial/Mesenchymal state in breast Cancer and its association with poor survival. PLoS One 10, e0126522 (2015)CrossRefPubMedPubMedCentral A. Grosse-Wilde, A. Fouquier d'Herouel, E. McIntosh, G. Ertaylan, A. Skupin, R.E. Kuestner, A. del Sol, K.A. Walters, S. Huang, Stemness of the hybrid epithelial/Mesenchymal state in breast Cancer and its association with poor survival. PLoS One 10, e0126522 (2015)CrossRefPubMedPubMedCentral
20.
go back to reference C. Villarroya-Beltri, F. Baixauli, C. Gutierrez-Vazquez, F. Sanchez-Madrid, M. Mittelbrunn, Sorting it out: Regulation of exosome loading. Semin Cancer Biol 28, 3–13 (2014)CrossRefPubMedPubMedCentral C. Villarroya-Beltri, F. Baixauli, C. Gutierrez-Vazquez, F. Sanchez-Madrid, M. Mittelbrunn, Sorting it out: Regulation of exosome loading. Semin Cancer Biol 28, 3–13 (2014)CrossRefPubMedPubMedCentral
21.
go back to reference D.W. Greening, S.K. Gopal, R.A. Mathias, L. Liu, J.Y. Sheng, H.J. Zhu, R.J. Simpson, Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression. Semin Cell Dev Biol 40, 60–71 (2015)CrossRefPubMed D.W. Greening, S.K. Gopal, R.A. Mathias, L. Liu, J.Y. Sheng, H.J. Zhu, R.J. Simpson, Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression. Semin Cell Dev Biol 40, 60–71 (2015)CrossRefPubMed
22.
go back to reference Y. Shao, Y. Shen, T. Chen, F. Xu, X. Chen, S. Zheng, The functions and clinical applications of tumor-derived exosomes. Oncotarget 7, 60736–60751 (2016)PubMedPubMedCentral Y. Shao, Y. Shen, T. Chen, F. Xu, X. Chen, S. Zheng, The functions and clinical applications of tumor-derived exosomes. Oncotarget 7, 60736–60751 (2016)PubMedPubMedCentral
23.
go back to reference V. Sundararajan, F.H. Sarkar, T.S. Ramasamy, The versatile role of exosomes in cancer progression: Diagnostic and therapeutic implications. Cell Oncol 41, 223–252 (2018)CrossRef V. Sundararajan, F.H. Sarkar, T.S. Ramasamy, The versatile role of exosomes in cancer progression: Diagnostic and therapeutic implications. Cell Oncol 41, 223–252 (2018)CrossRef
24.
go back to reference M. Sponziello, F. Rosignolo, M. Celano, V. Maggisano, V. Pecce, R.F. De Rose, G.E. Lombardo, C. Durante, S. Filetti, G. Damante, D. Russo, S. Bulotta, Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells. Mol Cell Endocrinol 431, 123–132 (2016)CrossRefPubMed M. Sponziello, F. Rosignolo, M. Celano, V. Maggisano, V. Pecce, R.F. De Rose, G.E. Lombardo, C. Durante, S. Filetti, G. Damante, D. Russo, S. Bulotta, Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells. Mol Cell Endocrinol 431, 123–132 (2016)CrossRefPubMed
25.
go back to reference M. Agajanian, F. Runa, J.A. Kelber, Identification of a PEAK1/ZEB1 signaling axis during TGFbeta/fibronectin-induced EMT in breast cancer. Biochem Biophys Res Commun 465, 606–612 (2015)CrossRefPubMed M. Agajanian, F. Runa, J.A. Kelber, Identification of a PEAK1/ZEB1 signaling axis during TGFbeta/fibronectin-induced EMT in breast cancer. Biochem Biophys Res Commun 465, 606–612 (2015)CrossRefPubMed
26.
go back to reference O. Tang, X.M. Chen, S. Shen, M. Hahn, C.A. Pollock, MiRNA-200b represses transforming growth factor-beta1-induced EMT and fibronectin expression in kidney proximal tubular cells. Am J Physiol Renal Physiol 304, F1266–F1273 (2013)CrossRefPubMed O. Tang, X.M. Chen, S. Shen, M. Hahn, C.A. Pollock, MiRNA-200b represses transforming growth factor-beta1-induced EMT and fibronectin expression in kidney proximal tubular cells. Am J Physiol Renal Physiol 304, F1266–F1273 (2013)CrossRefPubMed
27.
go back to reference M. Kajita, K.N. McClinic, P.A. Wade, Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 24, 7559–7566 (2004)CrossRefPubMedPubMedCentral M. Kajita, K.N. McClinic, P.A. Wade, Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 24, 7559–7566 (2004)CrossRefPubMedPubMedCentral
28.
go back to reference F.L. Graham, A.J. van der Eb, A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52, 456–467 (1973)CrossRefPubMed F.L. Graham, A.J. van der Eb, A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52, 456–467 (1973)CrossRefPubMed
30.
go back to reference J. Wang, Q. Wei, X. Wang, S. Tang, H. Liu, F. Zhang, M.K. Mohammed, J. Huang, D. Guo, M. Lu, F. Liu, J. Liu, C. Ma, X. Hu, R.C. Haydon, T.C. He, H.H. Luu, Transition to resistance: An unexpected role of the EMT in cancer chemoresistance. Genes Dis 3, 3–6 (2016)CrossRefPubMedPubMedCentral J. Wang, Q. Wei, X. Wang, S. Tang, H. Liu, F. Zhang, M.K. Mohammed, J. Huang, D. Guo, M. Lu, F. Liu, J. Liu, C. Ma, X. Hu, R.C. Haydon, T.C. He, H.H. Luu, Transition to resistance: An unexpected role of the EMT in cancer chemoresistance. Genes Dis 3, 3–6 (2016)CrossRefPubMedPubMedCentral
31.
go back to reference G. Repetto, A. del Peso, J.L. Zurita, Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc 3, 1125–1131 (2008)CrossRefPubMed G. Repetto, A. del Peso, J.L. Zurita, Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc 3, 1125–1131 (2008)CrossRefPubMed
32.
go back to reference C. Thery, S. Amigorena, G. Raposo, A. Clayton, Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Curr Protoc cell biol chapter 3. Unit 3, 22 (2006) C. Thery, S. Amigorena, G. Raposo, A. Clayton, Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Curr Protoc cell biol chapter 3. Unit 3, 22 (2006)
33.
go back to reference G. Akpinar, M. Kasap, N.Z. Canturk, M. Zulfigarova, E.E. Islek, S.A. Guler, T. Simsek, Z. Canturk, Proteomics analysis of tissue samples reveals changes in mitochondrial protein levels in parathyroid hyperplasia over adenoma. Cancer Genomics Proteomics 14, 197–211 (2017)CrossRefPubMedPubMedCentral G. Akpinar, M. Kasap, N.Z. Canturk, M. Zulfigarova, E.E. Islek, S.A. Guler, T. Simsek, Z. Canturk, Proteomics analysis of tissue samples reveals changes in mitochondrial protein levels in parathyroid hyperplasia over adenoma. Cancer Genomics Proteomics 14, 197–211 (2017)CrossRefPubMedPubMedCentral
34.
go back to reference X.F. Zheng, J.L. Carstens, J. Kim, M. Scheible, J. Kaye, H. Sugimoto, C.C. Wu, V.S. LeBleu and R. Kalluri, Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer, Nature 527, 525–530 (2015) X.F. Zheng, J.L. Carstens, J. Kim, M. Scheible, J. Kaye, H. Sugimoto, C.C. Wu, V.S. LeBleu and R. Kalluri, Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer, Nature 527, 525–530 (2015)
35.
go back to reference N.K. Kurrey, S.P. Jalgaonkar, A.V. Joglekar, A.D. Ghanate, P.D. Chaskar, R.Y. Doiphode, S.A. Bapat, Snail and slug mediate Radioresistance and Chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian Cancer cells. Stem Cells 27, 2059–2068 (2009)CrossRefPubMed N.K. Kurrey, S.P. Jalgaonkar, A.V. Joglekar, A.D. Ghanate, P.D. Chaskar, R.Y. Doiphode, S.A. Bapat, Snail and slug mediate Radioresistance and Chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian Cancer cells. Stem Cells 27, 2059–2068 (2009)CrossRefPubMed
36.
go back to reference Z.Y. Du, R.Y. Qin, C.F. Wei, M. Wang, C.J. Shi, R. Tian, C.H. Peng, Pancreatic Cancer cells resistant to Chemoradiotherapy rich in "stem-cell-like" tumor cells. Digest Dis Sci 56, 741–750 (2011)CrossRefPubMed Z.Y. Du, R.Y. Qin, C.F. Wei, M. Wang, C.J. Shi, R. Tian, C.H. Peng, Pancreatic Cancer cells resistant to Chemoradiotherapy rich in "stem-cell-like" tumor cells. Digest Dis Sci 56, 741–750 (2011)CrossRefPubMed
37.
go back to reference L.F. Zhu, Y. Hu, C.C. Yang, X.H. Xu, T.Y. Ning, Z.L. Wang, J.H. Ye and L.K. Liu, Snail overexpression induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells, Lab Invest 92, 744–752 (2012) L.F. Zhu, Y. Hu, C.C. Yang, X.H. Xu, T.Y. Ning, Z.L. Wang, J.H. Ye and L.K. Liu, Snail overexpression induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells, Lab Invest 92, 744–752 (2012)
38.
go back to reference U. Manne, T. Jadhav, B.D.K. Putcha, T. Samuel, S. Soni, C. Shanmugam, E.A. Suswam, Molecular biomarkers of colorectal Cancer and Cancer disparities: Current status and perspective. Curr Colorect Canc R 12, 332–344 (2016) U. Manne, T. Jadhav, B.D.K. Putcha, T. Samuel, S. Soni, C. Shanmugam, E.A. Suswam, Molecular biomarkers of colorectal Cancer and Cancer disparities: Current status and perspective. Curr Colorect Canc R 12, 332–344 (2016)
39.
go back to reference H. Chang, Y. Liu, M. Xue, H. Liu, S. Du, L. Zhang, P. Wang, Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition. Nucleic Acids Res 44, 2514–2527 (2016)CrossRefPubMedPubMedCentral H. Chang, Y. Liu, M. Xue, H. Liu, S. Du, L. Zhang, P. Wang, Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition. Nucleic Acids Res 44, 2514–2527 (2016)CrossRefPubMedPubMedCentral
40.
go back to reference Y. Pan, P. Liu, D. Chen, L. Dou, Small interfering RNA (siRNA) against slug induces apoptosis and sensitizes human anaplastic thyroid carcinoma cells to doxorubicin. Cancer Biomark 18, 357–366 (2017)CrossRefPubMed Y. Pan, P. Liu, D. Chen, L. Dou, Small interfering RNA (siRNA) against slug induces apoptosis and sensitizes human anaplastic thyroid carcinoma cells to doxorubicin. Cancer Biomark 18, 357–366 (2017)CrossRefPubMed
41.
go back to reference K. Tsukasa, Q. Ding, M. Yoshimitsu, Y. Miyazaki, S. Matsubara, S. Takao, Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133(+) pancreatic cancer cells. Hum Cell 28, 167–174 (2015)CrossRefPubMed K. Tsukasa, Q. Ding, M. Yoshimitsu, Y. Miyazaki, S. Matsubara, S. Takao, Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133(+) pancreatic cancer cells. Hum Cell 28, 167–174 (2015)CrossRefPubMed
42.
go back to reference D.P. Liang, T.Q. Huang, S.J. Li, Z.J. Chen, Knockdown of S100A4 chemosensitizes human laryngeal carcinoma cells in vitro through inhibition of slug. Eur Rev Med Pharmacol Sci 18, 3484–3490 (2014)PubMed D.P. Liang, T.Q. Huang, S.J. Li, Z.J. Chen, Knockdown of S100A4 chemosensitizes human laryngeal carcinoma cells in vitro through inhibition of slug. Eur Rev Med Pharmacol Sci 18, 3484–3490 (2014)PubMed
43.
go back to reference J. Pinkas, P. Leder, MEK1 signaling mediates transformation and metastasis of EpH4 mammary epithelial cells independent of an epithelial to mesenchymal transition. Cancer Res 62, 4781–4790 (2002)PubMed J. Pinkas, P. Leder, MEK1 signaling mediates transformation and metastasis of EpH4 mammary epithelial cells independent of an epithelial to mesenchymal transition. Cancer Res 62, 4781–4790 (2002)PubMed
44.
go back to reference P. Soulie, F. Carrozzino, M.S. Pepper, A.Y. Strongin, M.F. Poupon, R. Montesano, Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells. Oncogene 24, 1689–1697 (2005)CrossRefPubMed P. Soulie, F. Carrozzino, M.S. Pepper, A.Y. Strongin, M.F. Poupon, R. Montesano, Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells. Oncogene 24, 1689–1697 (2005)CrossRefPubMed
45.
go back to reference A. Garcia de Herreros, J. Baulida, Cooperation, amplification, and feed-back in epithelial-mesenchymal transition. Biochim Biophys Acta 1825, 223–228 (2012)PubMed A. Garcia de Herreros, J. Baulida, Cooperation, amplification, and feed-back in epithelial-mesenchymal transition. Biochim Biophys Acta 1825, 223–228 (2012)PubMed
46.
go back to reference J.H. Taube, J.I. Herschkowitz, K. Komurov, A.Y. Zhou, S. Gupta, J. Yang, K. Hartwell, T.T. Onder, P.B. Gupta, K.W. Evans, B.G. Hollier, P.T. Ram, E.S. Lander, J.M. Rosen, R.A. Weinberg, S.A. Mani, Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. P Natl Acad Sci USA 107, 15449–15454 (2010)CrossRef J.H. Taube, J.I. Herschkowitz, K. Komurov, A.Y. Zhou, S. Gupta, J. Yang, K. Hartwell, T.T. Onder, P.B. Gupta, K.W. Evans, B.G. Hollier, P.T. Ram, E.S. Lander, J.M. Rosen, R.A. Weinberg, S.A. Mani, Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. P Natl Acad Sci USA 107, 15449–15454 (2010)CrossRef
47.
go back to reference T.X. Dong, Y. Zhang, Y.D. Chen, P.F. Liu, T.T. An, J.W. Zhang, H.C. Yang, W.J. Zhu, X.H. Yang, FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition. Oncotarget 8, 1703–1713 (2017)PubMed T.X. Dong, Y. Zhang, Y.D. Chen, P.F. Liu, T.T. An, J.W. Zhang, H.C. Yang, W.J. Zhu, X.H. Yang, FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition. Oncotarget 8, 1703–1713 (2017)PubMed
48.
go back to reference W. Luo, X.N. Zhu, W. Liu, Y. Ren, C.H. Bei, L.Y. Qin, X.Y. Miao, F. Tang, G.F. Tang, S.K. Tan, MYC associated zinc finger protein promotes the invasion and metastasis of hepatocellular carcinoma by inducing epithelial mesenchymal transition. Oncotarget 7, 86420–86432 (2016)PubMedPubMedCentral W. Luo, X.N. Zhu, W. Liu, Y. Ren, C.H. Bei, L.Y. Qin, X.Y. Miao, F. Tang, G.F. Tang, S.K. Tan, MYC associated zinc finger protein promotes the invasion and metastasis of hepatocellular carcinoma by inducing epithelial mesenchymal transition. Oncotarget 7, 86420–86432 (2016)PubMedPubMedCentral
49.
go back to reference Z.H. Yang, B.C. Sun, Y.L. Li, X.L. Zhao, X.M. Zhao, Q. Gu, J.D. An, X.Y. Dong, F. Liu, Y. Wang, ZEB2 promotes vasculogenic mimicry by TGF-beta 1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma. Exp Mol Pathol 98, 352–359 (2015)CrossRefPubMed Z.H. Yang, B.C. Sun, Y.L. Li, X.L. Zhao, X.M. Zhao, Q. Gu, J.D. An, X.Y. Dong, F. Liu, Y. Wang, ZEB2 promotes vasculogenic mimicry by TGF-beta 1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma. Exp Mol Pathol 98, 352–359 (2015)CrossRefPubMed
50.
go back to reference J.K. Kim, H.Y. Jeon, H. Kim, The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res 38, 389–401 (2015)CrossRefPubMed J.K. Kim, H.Y. Jeon, H. Kim, The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res 38, 389–401 (2015)CrossRefPubMed
51.
go back to reference N.J.-p. Martin, S. Cotteret, C. Gaudin, M. Garrido, S. Aarab-Terrisse, N. al Nakouzi, L. Gentilini, D. Compagno, V. Ogryzko, G. Meurice, K. Fizazi, A. Chauchereau, Abstract 2995: Loss of SHISA3 is an early event of the epithelial-to-mesenchymal transition associated with chemoresistance in prostate cancer. Cancer Res 75, 2995–2995 (2015)CrossRef N.J.-p. Martin, S. Cotteret, C. Gaudin, M. Garrido, S. Aarab-Terrisse, N. al Nakouzi, L. Gentilini, D. Compagno, V. Ogryzko, G. Meurice, K. Fizazi, A. Chauchereau, Abstract 2995: Loss of SHISA3 is an early event of the epithelial-to-mesenchymal transition associated with chemoresistance in prostate cancer. Cancer Res 75, 2995–2995 (2015)CrossRef
52.
go back to reference Q. Wu, X. Wang, J. Liu, J.Y. Zheng, Y. Liu, Y.M. Li, F. Su, W.L. Ou, R. Wang, Nutlin-3 reverses the epithelial-mesenchymal transition in gemcitabine-resistant hepatocellular carcinoma cells. Oncol Rep 36, 1325–1332 (2016)CrossRefPubMed Q. Wu, X. Wang, J. Liu, J.Y. Zheng, Y. Liu, Y.M. Li, F. Su, W.L. Ou, R. Wang, Nutlin-3 reverses the epithelial-mesenchymal transition in gemcitabine-resistant hepatocellular carcinoma cells. Oncol Rep 36, 1325–1332 (2016)CrossRefPubMed
53.
go back to reference P.F. Zhang, K.S. Li, Y.h. Shen, P.T. Gao, Z.R. Dong, J.B. Cai, C. Zhang, X.Y. Huang, M.X. Tian, Z.Q. Hu, D.M. Gao, J. Fan, A.W. Ke, G.M. Shi, Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death &Amp; Disease 7, e2201 (2016) P.F. Zhang, K.S. Li, Y.h. Shen, P.T. Gao, Z.R. Dong, J.B. Cai, C. Zhang, X.Y. Huang, M.X. Tian, Z.Q. Hu, D.M. Gao, J. Fan, A.W. Ke, G.M. Shi, Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death &Amp; Disease 7, e2201 (2016)
54.
go back to reference T.H. Chang, M.F. Tsai, K.Y. Su, S.G. Wu, C.P. Huang, S.L. Yu, Y.L. Yu, C.C. Lan, C.H. Yang, S.B. Lin, C.P. Wu, J.Y. Shih and P.C. Yang, Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor, Am J Resp Crit Care 183, 1071–1079 (2011) T.H. Chang, M.F. Tsai, K.Y. Su, S.G. Wu, C.P. Huang, S.L. Yu, Y.L. Yu, C.C. Lan, C.H. Yang, S.B. Lin, C.P. Wu, J.Y. Shih and P.C. Yang, Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor, Am J Resp Crit Care 183, 1071–1079 (2011)
55.
go back to reference B. Uygur, K. Abramo, E. Leikina, C. Vary, L. Liaw, W.S. Wu, SLUG is a direct transcriptional repressor of PTEN tumor suppressor. Prostate 75, 907–916 (2015)CrossRefPubMedPubMedCentral B. Uygur, K. Abramo, E. Leikina, C. Vary, L. Liaw, W.S. Wu, SLUG is a direct transcriptional repressor of PTEN tumor suppressor. Prostate 75, 907–916 (2015)CrossRefPubMedPubMedCentral
56.
go back to reference A.M. Haslehurst, M. Koti, M. Dharsee, P. Nuin, K. Evans, J. Geraci, T. Childs, J. Chen, J. Li, J. Weberpals, S. Davey, J. Squire, P.C. Park, H. Feilotter, EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12, 91 (2012) A.M. Haslehurst, M. Koti, M. Dharsee, P. Nuin, K. Evans, J. Geraci, T. Childs, J. Chen, J. Li, J. Weberpals, S. Davey, J. Squire, P.C. Park, H. Feilotter, EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12, 91 (2012)
57.
go back to reference X.-Y. Zhao, L. Li, X.-B. Wang, R.-J. Fu, Y.-P. Lv, W. Jin, C. Meng, G.-Q. Chen, L. Huang and K.-W. Zhao, Inhibition of snail family transcriptional repressor 2 (SNAI2) enhances multidrug resistance of hepatocellular carcinoma cells, PLoS One 11, e0164752 (2016) X.-Y. Zhao, L. Li, X.-B. Wang, R.-J. Fu, Y.-P. Lv, W. Jin, C. Meng, G.-Q. Chen, L. Huang and K.-W. Zhao, Inhibition of snail family transcriptional repressor 2 (SNAI2) enhances multidrug resistance of hepatocellular carcinoma cells, PLoS One 11, e0164752 (2016)
58.
go back to reference A. Suetsugi, M. Nagaki, H. Aoki, T. Motohashi, T. Kunisada, H. Moriwaki, Characterization of CD133(+) hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Bioph Res Co 351, 820–824 (2006)CrossRef A. Suetsugi, M. Nagaki, H. Aoki, T. Motohashi, T. Kunisada, H. Moriwaki, Characterization of CD133(+) hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Bioph Res Co 351, 820–824 (2006)CrossRef
59.
go back to reference S. Ma, K.W. Chan, L. Hu, T.K.W. Lee, J.Y.H. Wo, I.L. Ng, B.J. Zheng, X.Y. Guan, Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542–2556 (2007)CrossRefPubMed S. Ma, K.W. Chan, L. Hu, T.K.W. Lee, J.Y.H. Wo, I.L. Ng, B.J. Zheng, X.Y. Guan, Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542–2556 (2007)CrossRefPubMed
60.
go back to reference W. Song, H. Li, K. Tao, R. Li, Z. Song, Q. Zhao, F. Zhang, K. Dou, Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract 62, 1212–1218 (2008)CrossRefPubMed W. Song, H. Li, K. Tao, R. Li, Z. Song, Q. Zhao, F. Zhang, K. Dou, Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract 62, 1212–1218 (2008)CrossRefPubMed
61.
go back to reference A. Mitra, J. Yan, X. Xia, S. Zhou, J. Chen, L. Mishra, S. Li, IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta-deficient beta2-spectrin+/− mice. Hepatology 65, 1222–1236 (2017)CrossRefPubMedPubMedCentral A. Mitra, J. Yan, X. Xia, S. Zhou, J. Chen, L. Mishra, S. Li, IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta-deficient beta2-spectrin+/− mice. Hepatology 65, 1222–1236 (2017)CrossRefPubMedPubMedCentral
64.
go back to reference M. Tajiri, S. Yoshida, Y. Wada, Differential analysis of site-specific glycans on plasma and cellular fibronectins: Application of a hydrophilic affinity method for glycopeptide enrichment. Glycobiology 15, 1332–1340 (2005)CrossRefPubMed M. Tajiri, S. Yoshida, Y. Wada, Differential analysis of site-specific glycans on plasma and cellular fibronectins: Application of a hydrophilic affinity method for glycopeptide enrichment. Glycobiology 15, 1332–1340 (2005)CrossRefPubMed
65.
go back to reference S. Xia, C. Wang, E.L. Postma, Y. Yang, X. Ni, W. Zhan, Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis. Onco Targets Ther 10, 1743–1755 (2017)CrossRefPubMedPubMedCentral S. Xia, C. Wang, E.L. Postma, Y. Yang, X. Ni, W. Zhan, Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis. Onco Targets Ther 10, 1743–1755 (2017)CrossRefPubMedPubMedCentral
66.
67.
go back to reference E. Sundquist, J.H. Kauppila, J. Veijola, R. Mroueh, P. Lehenkari, S. Laitinen, J. Risteli, Y. Soini, V.M. Kosma, I. Sawazaki-Calone, C.C. Macedo, R. Bloigu, R.D. Coletta, T. Salo, Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups. Br J Cancer 116, 640–648 (2017)CrossRefPubMedPubMedCentral E. Sundquist, J.H. Kauppila, J. Veijola, R. Mroueh, P. Lehenkari, S. Laitinen, J. Risteli, Y. Soini, V.M. Kosma, I. Sawazaki-Calone, C.C. Macedo, R. Bloigu, R.D. Coletta, T. Salo, Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups. Br J Cancer 116, 640–648 (2017)CrossRefPubMedPubMedCentral
68.
go back to reference N. Kanaji, N. Kita, N. Kadowaki, S. Bandoh, Fibronectin and hepatocyte growth factor produced by lung fibroblasts augment migration and invasion of malignant pleural mesothelioma cells. Anticancer Res 37, 2393–2400 (2017)CrossRefPubMed N. Kanaji, N. Kita, N. Kadowaki, S. Bandoh, Fibronectin and hepatocyte growth factor produced by lung fibroblasts augment migration and invasion of malignant pleural mesothelioma cells. Anticancer Res 37, 2393–2400 (2017)CrossRefPubMed
69.
go back to reference G.E. Jones, R.G. Arumugham, M.L. Tanzer, Fibronectin glycosylation modulates fibroblast adhesion and spreading. J Cell Biol 103, 1663–1670 (1986)CrossRefPubMed G.E. Jones, R.G. Arumugham, M.L. Tanzer, Fibronectin glycosylation modulates fibroblast adhesion and spreading. J Cell Biol 103, 1663–1670 (1986)CrossRefPubMed
70.
go back to reference C.J. Clarke, T.J. Berg, J. Birch, D. Ennis, L. Mitchell, C. Cloix, A. Campbell, D. Sumpton, C. Nixon, K. Campbell, V.L. Bridgeman, P.B. Vermeulen, S. Foo, E. Kostaras, J.L. Jones, L. Haywood, E. Pulleine, H. Yin, D. Strathdee, O. Sansom, K. Blyth, I. McNeish, S. Zanivan, A.R. Reynolds, J.C. Norman, The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr Biol 26, 755–765 (2016)CrossRefPubMedPubMedCentral C.J. Clarke, T.J. Berg, J. Birch, D. Ennis, L. Mitchell, C. Cloix, A. Campbell, D. Sumpton, C. Nixon, K. Campbell, V.L. Bridgeman, P.B. Vermeulen, S. Foo, E. Kostaras, J.L. Jones, L. Haywood, E. Pulleine, H. Yin, D. Strathdee, O. Sansom, K. Blyth, I. McNeish, S. Zanivan, A.R. Reynolds, J.C. Norman, The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr Biol 26, 755–765 (2016)CrossRefPubMedPubMedCentral
71.
go back to reference T. Yoshida, M. Hashimura, T. Kuwata, T. Matsumoto, E. Suzuki, Y. Tazo, H. Nakajima, M. Inukai, M. Saegusa, Transcriptional regulation of the alpha-1 type II collagen gene by nuclear factor B/p65 and Sox9 in the chondrocytic phenotype of uterine carcinosarcomas. Hum Pathol 44, 1780–1788 (2013)CrossRefPubMed T. Yoshida, M. Hashimura, T. Kuwata, T. Matsumoto, E. Suzuki, Y. Tazo, H. Nakajima, M. Inukai, M. Saegusa, Transcriptional regulation of the alpha-1 type II collagen gene by nuclear factor B/p65 and Sox9 in the chondrocytic phenotype of uterine carcinosarcomas. Hum Pathol 44, 1780–1788 (2013)CrossRefPubMed
72.
go back to reference S. Muller, S. Soder, A.M. Oliveira, C.Y. Inwards, T. Aigner, Type II collagen as specific marker for mesenchymal chondrosarcomas compared to other small cell sarcomas of the skeleton. Mod Pathol 18, 1088–1094 (2005)CrossRefPubMed S. Muller, S. Soder, A.M. Oliveira, C.Y. Inwards, T. Aigner, Type II collagen as specific marker for mesenchymal chondrosarcomas compared to other small cell sarcomas of the skeleton. Mod Pathol 18, 1088–1094 (2005)CrossRefPubMed
73.
go back to reference W.L. Zhu, B.L. Fan, D.L. Liu, W.X. Zhu, Abnormal expression of fibrinogen gamma (FGG) and plasma level of fibrinogen in patients with hepatocellular carcinoma. Anticancer Res 29, 2531–2534 (2009)PubMed W.L. Zhu, B.L. Fan, D.L. Liu, W.X. Zhu, Abnormal expression of fibrinogen gamma (FGG) and plasma level of fibrinogen in patients with hepatocellular carcinoma. Anticancer Res 29, 2531–2534 (2009)PubMed
Metadata
Title
Identification of biomarkers associated with partial epithelial to mesenchymal transition in the secretome of slug over-expressing hepatocellular carcinoma cells
Authors
Oğuzhan Karaosmanoğlu
Sreeparna Banerjee
Hülya Sivas
Publication date
01-08-2018
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 4/2018
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-018-0384-6

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