Advanced search
Start date
Betweenand

Analysis of TIMP1 N-aberrant glycosylation and its role in the progression of melanoma

Grant number: 20/01211-9
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2020
Effective date (End): March 31, 2021
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Miriam Galvonas Jasiulionis
Grantee:Beatriz Laís Justo Saraiva
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Skin cancer is the most frequent cancer in Brazil, corresponding to about one third of all cases of malignant neoplasms registered in the country. One skin cancer type is melanoma, which, although representing only 3% of malignant tumors that occur in this organ, is the most serious type of skin cancer due to its high capacity to metastasize and, as a consequence, has a high lethality power. Melanoma originates from the malignant transformation of melanocytes, cells located on the basal layer of epidermis, and responsible for melanin synthesis. It is believed that the progression from a healthy to a premalignant melanocyte occurs when these melanocytes lose their ability to interact with keratinocytes, and extracellular matrix. This characteristic of cell-cell and cell-matrix interactions independent survival results in anoikis resistance, which gives these cells the power to form metastases. In our laboratory, we used cell lines established from melanocytes malignant transformation induced by sequential impediment of cell-cell and cell-matrix interactions. Cell lines corresponding to different stages of melanoma progression were obtained by subjecting non-tumorigenic melanocytes (melan-a) to sequential cycles of adhesion impediment. A study carried out in our laboratory showed increase in TIMP1 expression along melanocytes malignant transformation. Thus, it was demonstrated that high levels of TIMP1, in our model, provide resistance to cell death and favor the occurrence of metastases. After studies of the importance of TIMP1 in melanoma progression, it has been shown that TIMP1 forms, with CD63 and ²1-integrin, a supramolecular complex in the cell membrane, as the melanoma progresses. This complex was observed acting on the activation of intracellular signaling pathways for survival and resistance, with the participation of PDK1 and AKT, which protect cells from anoikis. In addition, the presence of N-aberrant glycosylation has been detected in TIMP1 and other glycoproteins that are related to resistance to anoikis and tumor cell survival, including CD63 and ²1-integrins, in other types of cancer, such as human colon. Thus, this project aims to analyze the presence of N-aberrant glycosylation in TIMP1 in cell lines that represent the melanoma progression model and understand how this aberrant N-glycosylation interferes with the roles that TIMP1 plays in progression, survival and anoikis resistance in melanoma. (AU)