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Oncol Lett. 2021 Jul;22(1):551.
Oncol Lett. 2021 Jul;22(1):551.
Changes in SLIT2 expression are associated with the migration of human ovarian clear cell carcinoma cells
Changes in SLIT2 expression are associated with the migration of human ovarian clear cell carcinoma cells
Ovarian clear cell carcinoma (OCCC) is characterized by a poor survival of patients, which is mainly due to metastasis and treatment failure. Slit guidance ligand 2 (SLIT2), a secreted protein, has been reported to modulate the migration of neural cells and human cancer cells. However, the effect of changes in SLIT2 expression on the regulation of cell migration in OCCC remains unknown. The present study examined alterations in SLIT2 expression using OCCC cell models, including low- and high-mobility SKOV3 cells, as well as OCCC tissues. DNA methylation analysis suggested that promoter hypermethylation was responsible for the low expression levels of SLIT2 in OCCC cells. The demethylating agent 5-Aza-deoxycytosine was able to restore SLIT2 expression at both the mRNA and protein levels in high-mobility SKOV3 cells that harbored the relevant methylated promoter. Overexpression of SLIT2 inhibited the migration of high-mobility OCCC cells, as well as decreased the protein expression levels of β-catenin, phosphorylated (p)AKT and snail family transcriptional repressor 1 (SNAI1). On the other hand, knockdown of SLIT2 increased the migration of low-mobility OCCC cells, and enhanced the protein expression levels of β-catenin, pAKT and SNAI1. Overall, the results of the present study provided evidence that low expression levels of SLIT2 were associated with increased OCCC cell migration, and that SLIT2 may act as a suppressor gene of cancer cell migration.
Figure 1. Mobility of ovarian clear cell carcinoma cells and epigenetic alteration of SLIT2. (A) Gap closure and (B) adhesion assays were conducted using SKOV3-L and SKOV3-H cells. (C) Protein expression levels of SLIT2. (D) mRNA expression levels of SLIT2. (E) DNA hypermethylation of the SLIT2 gene. (F) Effects of the treatment of SKOV3-H cells with the demethylating agent 5-aza-dC. The primer sets used for amplification are designated as ‘U’ for the unmethylated gene or ‘M’ for the methylated gene. The P-value for each analysis was obtained using a two-tailed unpaired t-test. Quantitative data are presented as the mean ± SD from three independent experiments. **P<0.01 vs. SKOV-L. SLIT2, slit guidance ligand 2; SKOV3-L, low-mobility SKOV3 cells; SKOV3-H, high-mobility SKOV3 cells; 5-aza-dC, 5-aza-2’-deoxycytidine; OD, optical density.
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