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

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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.

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Acknowledgements

We are grateful to Prof. Dr. Mehmet ÖZTÜRK (Dokuz Eylül University, İzmir, Turkey) for generously providing Huh7 cells, to Prof. Dr. Murat KASAP (Kocaeli University, Kocaeli, Turkey) for carrying out the MALDI-TOF/TOF experiments, to Ilir SHERAJ (Middle East Technical University, Ankara, Turkey) for bioinformatics analyses and to Melis ÇOLAKOĞLU (Middle East Technical University, Ankara, Turkey) for help with the Western blots. This study was supported by the Anadolu University (1508F587) and a Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TUBİTAK) 2211-C grant.

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  1. Department of Biology, Faculty of Science, Anadolu University, 26400, Eskişehir, Turkey

    Oğuzhan Karaosmanoğlu & Hülya Sivas

  2. Department of Biological Sciences, Faculty of Science and Letters, Middle East Technical University, 06800, Ankara, Turkey

    Sreeparna Banerjee

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  1. Oğuzhan Karaosmanoğlu
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Oğuzhan Karaosmanoğlu carried out the experiments and wrote the manuscript, Sreeparna Banerjee supervised the research and wrote the manuscript, and Hülya Sivas was responsible for the overall supervision of the research.

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Correspondence to Oğuzhan Karaosmanoğlu.

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Karaosmanoğlu, O., Banerjee, S. & Sivas, H. Identification of biomarkers associated with partial epithelial to mesenchymal transition in the secretome of slug over-expressing hepatocellular carcinoma cells. Cell Oncol. 41, 439–453 (2018). https://doi.org/10.1007/s13402-018-0384-6

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