Endometriosis shares many of the hallmarks of cancer, including metastatic potential, dysregulated growth, and angiogenesis. Preliminary studies in our laboratory and others have shown that lysyl oxidase (LOX) and lysyl oxidase like 1 (LOXL1) gene expression is increased in endometrioitic lesions from patients and in an animal model of disease. Lysyl oxidases are a family of extracellular amine oxidases, which mediate the formation of insoluble collagen and elastin in the extracellular matrix. In addition to this role, lysyl oxidases have been ascribed roles in cell growth regulation, differentiation and cell migration. Recently, LOX isoforms have been identified as new players in the regulation of epithelial-mesenchymal transition (EMT), a mechanism whereby cancer cells become migratory and invasive. LOX isoforms have been shown to cooperate with the transcription factor Snail to downregulate E-cadherin expression, an important determinant of the invasion process of epithelial tumors, via interactions with the well-conserved C-terminal end. LOX expression has been correlated to increased in vitro invasion capacity of human breast cancer cells. Specifically, this study aims to investigate whether lox's isoforms (LOX and LOXL1) exert a growth- regulatory, invasiveness-promoting role in endometrial cells. The main hypothesis driving this proposal is that increased levels of LOX and LOXL1 results in a reduction in the expression of E-cadherin via interactions with Snail, which promotes the highly invasive, metastatic phenotype that characterizes endometriotic cells. We also hypothesize that the expression of LOX and LOXL1 is normally regulated during the menstrual cycle by estradiol and progesterone. To test these hypotheses, first we will determine the basal pattern of expression of LOX and LOXL1 in human endometrial cells and their regulation by steroid hormones (Specific Aim #1). To determine whether upregulation of LOXs plays a role in growth and invasive potential of endometrial cells, we will transfect human endometrial cell lines with LOX and LOXL1 genes and measure proliferation, cell migration, and increased expression of genes involved in the metastatic process (Specific Aim #2).
In Specific Aim #3, we will determine if LOX and LOXL1 expression activate Snail to downregulate E-cadherin expression and induce epithelial to mesenchymal transitions (EMT) in human endometrial stromal and epithelial cells. This knowledge is important to understand how endometrial cells are able to survive, grow in the peritoneum and metastasize to other organs, causing a painful, poorly understood disease known as endometriosis. ? ? ?
|Ruiz, Lynnette A; Báez-Vega, Perla M; Ruiz, Abigail et al. (2015) Dysregulation of Lysyl Oxidase Expression in Lesions and Endometrium of Women With Endometriosis. Reprod Sci 22:1496-508|
|Colón-Díaz, Maricarmen; Báez-Vega, Perla; García, Miosotis et al. (2012) HDAC1 and HDAC2 are differentially expressed in endometriosis. Reprod Sci 19:483-92|