Tissue Inhibitor of Metalloproteinase 1 Expression Associated with Gene Demethylation Confers Anoikis Resistance in Early Phases of Melanocyte Malignant Transformation

Author(s)

Ricca, Tatiana I. ^[1] ; Liang, Gangning ^[2] ; Suenaga, Ana Paula M. ^[3] ; Han, Sang W. ^[4] ; Jones, Peter A. ^[2] ; Jasiulionis, Miriam G. ^{[1, 5]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, BR-04023900 Sao Paulo - Brazil

^[2] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 - USA

^[3] Univ Fed Sao Paulo, Dept Biochem, BR-04023900 Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Ctr Interdisciplinar Terapia Genica, BR-04023900 Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Pharmacol, BR-04023900 Sao Paulo - Brazil

• Document type: Journal article
• Source: TRANSLATIONAL ONCOLOGY; v. 2, n. 4, p. 329-340, DEC 2009.
• Web of Science Citations: 16

Abstract

Although anoikis resistance has been considered a hallmark of malignant phenotype, the causal relation between neoplastic transformation and anchorage-independent growth remains undefined. We developed an experimental model of murine melanocyte malignant transformation, where a melanocyte lineage (melan-a) was submitted to sequential cycles of anchorage blockade, resulting in progressive morphologic alterations, and malignant transformation. Throughout this process, cells corresponding to premalignant melanocytes and melanoma cell lines were established and show progressive anoikis resistance and increased expression of Timp1. In melan-a melanocytes, Timp1 expression is suppressed by DNA methylation as indicated by its reexpression after 5-aza-2'-deoxycytidine treatment. Methylation-sensitive single-nucleotide primer extension analysis showed increased demethylation in Timp1 in parallel with its expression along malignant transformation. Interestingly, TIMP1 expression has already been related with negative prognosis in some human cancers. Although described as aMMP inhibitor, this protein has been associated with apoptosis resistance in different cell types. Melan-a cells overexpressing Timp1 showed increased survival in suspension but were unable to form tumors in vivo, whereas Timp1-overexpressing melanoma cells showed reduced latency time for tumor appearance and increased metastatic potential. Here, we demonstrated for the first time an increment in Timp1 expression since the early phases of melanocyte malignant transformation, associated to a progressive gene demethylation, which confers anoikis resistance. In this way, Timp1 might be considered as a valued marker for melanocyte malignant transformation. (AU)

• FAPESP's process: 06/61293-1 - DNA methylation contribution to carcinogenesis
• Grantee: Miriam Galvonas Jasiulionis
• Support Opportunities: Research Grants - Young Investigators Grants