Expression profiling of Galectin-3-depleted melanoma cells reveals its major role in melanoma cell plasticity and vasculogenic mimicry.
Galectin-3 (Gal-3) is a beta-galactoside-binding protein that is involved in cancer progression and metastasis. Using a progressive human melanoma tissue microarray, we previously demonstrated that melanocytes accumulate Gal-3 during the progression from benign to dysplastic nevi to melanoma and further to metastatic melanoma. Herein, we show that silencing of Gal-3 expression with small hairpin RNA results in a loss of tumorigenic and metastatic potential of melanoma cells. In vitro, Gal-3 silencing resulted in loss of tumor cell invasiveness and capacity to form tube-like structures on collagen ("vasculogenic mimicry"). cDNA microarray analysis after Gal-3 silencing revealed that Gal-3 regulates the expression of multiple genes, including endothelial cell markers that appear to be aberrantly expressed in highly aggressive melanoma cells, causing melanoma cell plasticity. These genes included vascular endothelial-cadherin, which plays a pivotal role in vasculogenic mimicry, as well as interleukin-8, fibronectin-1, endothelial differentiation sphingolipid G-protein receptor-1, and matrix metalloproteinase-2. Chromatin immunoprecipitation assays and promoter analyses revealed that Gal-3 silencing resulted in a decrease of vascular endothelial-cadherin and interleukin-8 promoter activities due to enhanced recruitment of transcription factor early growth response-1. Moreover, transient overexpression of early growth response-1 in C8161-c9 cells resulted in a loss of vascular endothelial-cadherin and interleukin-8 promoter activities and protein expression. Thus, Gal-3 plays an essential role during the acquisition of vasculogenic mimicry and angiogenic properties associated with melanoma progression.
Mourad-Zeidan
Alexandra A
AA
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Melnikova
Vladislava O
VO
Wang
Hua
H
Raz
Avraham
A
Bar-Eli
Menashe
M
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000033:anatomy & histology; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D037502:Galectin 3; D016209:Interleukin-8; D000099152:Cadherin 5