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

• Grant number: 20/01211-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2020
• End date: August 31, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Miriam Galvonas Jasiulionis
• Grantee: Beatriz Laís Justo Saraiva
• Host 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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

JUSTO, BEATRIZ LAIS; JASIULIONIS, MIRIAM GALVONAS. Characteristics of TIMP1, CD63, and beta 1-Integrin and the Functional Impact of Their Interaction in Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 17, SEP 2021. (20/01211-9, 18/20775-0)