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Projects / Programmes source: ARIS

Role of cysteine proteases in the process of cancerogenesis

Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
B000  Biomedical sciences   

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
cancer, cancerogenesis, proteolysis, proteases, cathepsins, proteomics, biomarkers
Evaluation (rules)
source: COBISS
Researchers (12)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Head  2013 - 2016  188 
2.  35024  PhD Michal Piotr Potempa  Biochemistry and molecular biology  Researcher  2013 
3.  34315  Gregor Pretnar    Technical associate  2014  13 
4.  34212  PhD Jelena Rajković  Biochemistry and molecular biology  Researcher  2014 - 2016  21 
5.  29542  PhD Barbara Sobotič  Biochemistry and molecular biology  Researcher  2013 - 2016  62 
6.  07561  PhD Boris Turk  Biochemistry and molecular biology  Researcher  2013 - 2016  1,038 
7.  01085  PhD Vito Turk  Biochemistry and molecular biology  Researcher  2013  1,490 
8.  21619  PhD Olga Vasiljeva  Oncology  Researcher  2013 - 2016  183 
9.  33762  PhD Robert Vidmar  Biochemistry and molecular biology  Technical associate  2013 - 2016  149 
10.  32171  PhD Matej Vizovišek  Biochemistry and molecular biology  Researcher  2013 - 2016  143 
11.  37161  Tanja Vrabič  Microbiology and immunology  Researcher  2016 
12.  03368  PhD Eva Žerovnik  Biochemistry and molecular biology  Researcher  2014 - 2016  391 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,059 
2.  2990  Center of excellence for integrated approaches in chemistry and biology of proteins, Ljubljana  Ljubljana  3663388  727 
Abstract
Proteases play a crucial role in cell surface signaling pathways and extracellular matrix remodeling. Cell surface proteins can be activated, inactivated or can undergo other changes in their function upon proteolysis. Cysteine cathepsins are a group of papain-like cysteine proteases, which are mainly located within the endosomes/lysosomes. They execute non-specific bulk proteolysis and participate in numerous specific physiological processes such as protein processing, antigen presentation and processing, bone remodeling and apoptosis. In certain pathological states such as cancer, cathepsins can be translocated to the cellular membrane or secreted in the extracellular space, where they are known to promote angiogenesis, proliferation and tumor invasion. Only a few extracellular cathepsin substrates have been identified to date and their exact role in cancerogenesis still remains largely unknown. In the course of our previous work (project J1-0185), we have used proteomic approach for identification of cell surface cathepsin substrates, that led to the identification of a novel group of membrane protein substrates for cathepsins L, S and B (manuscript in preparation). We were the first who have shown that cathepsins can act like sheddases and cleave specific protein domains from the cell surface. We have also shown that cathepsin extracellular activity directly promotes cancer invasion. Among identified cathepsin substrates are receptors (CD71, CD109, plexins, ephrin receptors, neuropilins), adhesion proteins (CD44, CAM proteins) and desmosome/hemidesmosome components (plectin, plakins, cytokeratins). The majority of identified susbstrates is known to be involved in cancer progression. The main goal of the proposed research is the identification and validation of signaling pathways involving the identified substrates and expansion our substrate search to other interesting cysteine proteases (cathepsins K, V and legumain). Since it is well documented that cysteine proteases play an important role in the process of cancerogenesis, we believe that a deeper physiological characterization of those proteolytic events will provide a completely novel insight into the regulation of cancer development at the molecular level. Results of the proposed project would likely reveal novel cancer biomarkers and open the way towards new therapeutical approaches for cancer treatment. We are convinced that our findings will achieve high international impact. Novel scientific approaches applied in this project will benefit not only our field of research but also the entire Slovenian scientific community.
Significance for science
Cysteine proteases have been identified as important players in the process of cancer progression. Although they are known to promote invasion, proliferation, apoptosis and angiogenesis, their exact mode of action still remains largely unknown since only a few of their physiological substrates have been identified to date. In the case of legumain, even its regular physiological function is poorly understood and observed pH dependant specificity switch could have significant implications in its physological role. Research performed in this project revealed several new substrates of cysteine cathepsins and legumain which could explain observed phenotypes of cathepsin and legumain knockout mice. We have revealed membrane substrates which connect extracellular cysteine protease activity with intracellular signaling and shown that they can influence small GTPase activity. Our research has therefore provided a novel insight into molecular mechanisms of cysteine protease action and its role in cancer progression. Furthermore, it has opened numerous interesting possibilities for further competitive research in cancer related projects. The study performed on clinical samples of colon cancer has also shown possible application of cleaved substrates as prognostic or diagnostic markers.
Significance for the country
Although proteomic and degradomic experimental approaches became a fundamental part of modern life sciences research, their applicability in Slovenia still remains limited due to the general lack of methodological expertise and availability of appropriate instrumentation. Our laboratory is currently the only academic institution in Slovenia capable of performing in house mass spectrometry based proteomic analysis of complex biological samples. In the course of this project we have not only improved our expertise in standard quantitative proteomic methodologies such as SILAC and label-free quantification but also for the first time introduced modern degradomic approaches such as COFRADIC and PROTOMAP. Furthermore, it provided us an opportunity to develop novel degradomic methodologies (FPPS, DIPPS), which were shown to outperform many of the other well established protocols. By working on this project we were able to further develop our data processing skills by introducing Maxquant and PEAKS database search engines in our work. As a consequence of our efforts we were the first Slovenian research group which published their work in the Molecular and Cellular Proteomics which is the most prestigious proteomic journal. Slovenian research agency (ARRS) also declared this publication as one of the excellent scientific achievements in the year 2015. The know-how which was obtained through this project will be disseminated through our numerous collaborations with other Slovenian research institutions as well as pharmaceutical and biotechnological companies. In the course of this project, three graduate students were trained in proteomic methodology and obtained their PhD. We are confident, that the expertise obtained through this project will enrich Slovenian research community and strongly benefit our technological advancement. It will also increase our competitiveness for participation in leading international research projects.
Most important scientific results Annual report 2013, 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2013, 2014, 2015, final report
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