Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer

2019-09
Kagiali, Zeynep Cansu Üretmen
Sanal, Erdem
Karayel, Özge
Polat, Ayşe Nur
Saatçi, Özge
Ersan, Pelin Gülizar
Trappe, Kathrin
Renard, Bernhard Y.
Önder, Tamer T.
Tunçbağ, Nurcan
Şahin, Özgür
Özlü, Nurhan
Show full item record
475
views
176
downloads
Epithelial-mesenchymal transition (EMT) is driven by complex signaling events that induce dramatic biochemical and morphological changes whereby epithelial cells are converted into cancer cells. However, the underlying molecular mechanisms remain elusive. Here, we used mass spectrometry based quantitative proteomics approach to systematically analyze the post-translational biochemical changes that drive differentiation of human mammary epithelial (HMLE) cells into mesenchymal. We identified 314 proteins out of more than 6,000 unique proteins and 871 phosphopeptides out of more than 7,000 unique phosphopeptides as differentially regulated. We found that phosphoproteome is more unstable and prone to changes during EMT compared with the proteome and multiple alterations at proteome level are not thoroughly represented by transcriptional data highlighting the necessity of proteome level analysis. We discovered cell state specific signaling pathways, such as Hippo, sphingolipid signaling, and unfolded protein response (UPR) by modeling the networks of regulated proteins and potential kinase-substrate groups. We identified two novel factors for EMT whose expression increased on EMT induction: DnaJ heat shock protein family (Hsp40) member B4 (DNAJB4) and cluster of differentiation 81 (CD81). Suppression of DNAJB4 or CD81 in mesenchymal breast cancer cells resulted in decreased cell migration in vitro and led to reduced primary tumor growth, extravasation, and lung metastasis in vivo. Overall, we performed the global proteomic and phosphoproteomic analyses of EMT, identified and validated new mRNA and/ or protein level modulators of EMT. This work also provides a unique platform and resource for future studies focusing on metastasis and drug resistance
Tumor-Suppressor, Drug-Resistance, Stem-Cells, Protein, Enrichment, Emt, Mechanisms, Inhibition, Resource, Platform
https://hdl.handle.net/11511/28657
https://dx.doi.org/10.1074/mcp.RA119.001446
Molecular and Cellular Proteomics
Graduate School of Informatics, Article

Suggestions

Systematically organized nanopillar arrays reveal differences in adhesion and alignment properties of BMSC and Saos-2 cells
Ozcelik, Hayriye; Padeste, Celestino; Hasırcı, Vasıf Nejat (2014-07-01)
Polymeric test surfaces of P(L-D,L)LA and of a P(L-D,L)LA:PLGA blend decorated with 25 nanopillar covered fields, were used to investigate differences in growth of bone marrow stem cells (BMSC) and osteosarcoma cells (Saos-2). The fields were populated with pillars (ca. 900 nm tall, 200 nm x 200 nm area) separated systematically from each other with 1-10 mu m gaps. Saos-2 cells populated fields decorated with pillars 1 mu m apart but they avoided pillar-free surfaces. In contrast, BMSCs avoided fields with ...
Investigation of the role of programmed cell death 10 (PDCD10) protein in multidrug resistance
Urfalı Mamatoğlu, Çağrı; Gündüz, Ufuk; Department of Biology (2018)
Drug resistance, a major obstacle in chemotherapy, is the sum of several cellular alterations including resistance to induction of apoptosis. Apoptosis is a well-regulated cell death mechanism which is controlled by several signaling pathways and a vast number of proteins. Alterations in the proteins involved in the apoptotic regulation have been associated with drug resistance in cancer. Programmed Cell Death 10 (PDCD10) protein is a novel apoptotic regulator that is recently linked to the modulation of ce...
Meta analysis of alzheimer’s disease at the gene expression level
İzgi, Hamit; Somel, Mehmet; Department of Biology (2017)
In this study, publicly available microarray gene expression datasets are used to investigate common gene expression changes in different postmortem brain regions in Alzheimer’s Disease (AD) patients compared to control subjects, and to find possible functional associations related to these changes. The hypothesis is that pathogenesis of the disease converges into common patterns of dysregulation/alteration or dysfunction in molecular pathways across different brain regions in AD. In total, I studied 13 dat...
Different Types of Cell Cycle- and Apoptosis-Related Gene Expressions Alter in Corticosteroid-, Vincristine-, and Melphalan-Resistant U-266 Multiple Myeloma Cell Lines
Mutlu, Pelin; Gündüz, Ufuk (2014-09-01)
Objective: Deregulation of the cell cycle and apoptosis mechanisms in normal cells causes many problems, including cancer. In this study, a genome-wide expression analysis of cell cycle- and apoptosis-related genes in corticosteroid-, vincristine-, and melphalan-resistant U-266 multiple myeloma cell lines was conducted.
Characterization and identification of human mesenchymal stem cells at molecular level
Aksoy, Ceren; Severcan, Feride; Çetinkaya, Duygu Uçkan; Department of Biotechnology (2012)
Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent cells that can differentiate into a variety of non-hematopoietic tissues. They also maintain healthy heamatopoiesis by providing supportive cellular microenvironment into BM. In this thesis, MSCs were characterized in terms of their morphological, immunophenotypical and differentiation properties. Then, they were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy together with hierarchical clustering, and FT...
Citation Formats
Z. C. Ü. Kagiali et al., “Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer,” Molecular and Cellular Proteomics, 2019, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/28657.
METU IIS - Integrated Information Service open@metu.edu.tr