CEACAM1 promotes melanoma metastasis and is involved in the regulation of the EMT associated gene network in melanoma cells

Abstract

We investigated the functional role of CEACAM1 in a spontaneous metastasis xenograft model of human melanoma in scid mice using BRAF wildtype MeWo cells with and without RNAi mediated knockdown of CEACAM1. Tumors from the xenograft model were subjected to whole genome expression analysis and metastasis was quantified histologically. Results and identified markers were verified using tissue samples of over 100 melanoma patients. Knockdown of CEACAM1 prolonged the animals’ survival by significantly reducing subcutaneous growth of MeWo tumors and spontaneous lung metastasis. Microarray analysis revealed a strong influence of CEACAM1 knockdown on the network of EMT associated genes in the xenograft tumors (e.g. downregulation of BRAF, FOSL1, NRAS and TWIST). IGFBP7 and Latexin (highest up- and downregulated expression in microarray analysis) were found to be associated with longer and shorter survival, respectively, of melanoma patients. High FOSL1 and altered TWIST1 expression were found to be correlated with shortened survival in the cohort of melanoma patients. After a stepwise selection procedure combining above markers, multivariate analysis revealed IGFBP7, Latexin and altered TWIST to be prognostic markers for death. CEACAM1 could be a target for melanoma therapy as an alternative to (or in combination with) immune checkpoint and BRAF inhibitors.

Immune checkpoint blockade therapies for HCC: current status and future implications

“…Chen et al [105] demonstrated that EMT positive human esophageal cancer tissues had higher PD-L1 expression compared to an EMT negative subgroup. Similar studies have shown an association between EMT and immune checkpoint expression in several cancers including thymic carcinoma [106] , melanoma [107] , adeno cystic carcinoma [108] , extrahepatic cholangiocarcinoma [109] and renal cell carcinoma [110] .…”

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

“…Interrogating expression of 168 genes using the RT 2 Profiler TM PCR expression array technology, significant changes at the mRNA level affecting twenty-one EMT-related genes were detected [(upregulated): CDH1 , OCLN , IL1RN, PDGFRB, SNAI3 ; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05; Figure 3 A: volcano plot; Figure 3 B: table)]. Strikingly, these genes modulated by GLO1 _KO status encode various factors involved in EMT-like dynamics, as detailed in the discussion [ 13 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Taken together, these expression changes are consistent with EMT suppression as a result of GLO1 deletion.…”

“…Strikingly, differential gene expression array analysis (A375- GLO1 -KO versus A375- GLO1 -WT) revealed pronounced modulation of EMT-related genes ( Figure 3 ). These genes are encoding: ( I ) cellular adhesion factors, signaling molecules, and extracellular matrix components (including BMP1, CTNNB1, CDH1, FN1, FZD7, IL1RN, CDH2, VIM, WNT5A ); ( II ) enzymes involved in extracellular matrix remodeling (including MMP2, MMP9 ) and inflammation ( PTGS2 ); ( III ) transcription factors (including MYC, SNAI2, SNAI3, TWIST1, ZEB1, ZEB2 ); ( IV ) iron-regulatory factors (including FTH1, MELTF, TFRC )—all of which have been shown earlier to control cellular EMT and invasiveness in various tumor types [ 13 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

“…EMT is now an established molecular pathway involved in melanoma progression, recognized also as an important therapeutic target, and our array analysis identified a number of EMT-regulatory genes responsive to GLO1 status implicated mechanistically in metastatic melanoma [ 13 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. The fact that these gene expression changes (associated with attenuation of EMT-potential) occur as a direct result of GLO1 deletion was further substantiated by the fact that GLO1 re-expression (A375- GLO1 -R versus A375- GLO1 -KO) largely reversed this expression pattern ( Figure 7 ).…”

Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer: An Integrated Bioinformatics Analysis

“…It has been reported that ECM components such as collagen, broblasts and their associated signaling molecules contribute to tumor cell proliferation, migration and invasion in various cancers [40,41]. Moreover, IGFBP7 has been reported to regulate epithelial-mesenchylmal transition (EMT) in some solid tumors [12,42,43]. The above results suggest that IGFBP7 and its coexpressed genes may be involved in ECM-related pathways, which would contribute to the utility of IGFBP7 to predict poor prognosis of GC.…”