Chronic lymphocytic leukemia (CLL) is one of the most often diagnosed hematological malignant tumors in the Western world and a type of inert B-cell lymphoma that commonly attacks the elderly. Small ubiquitin related modifier (SUMO)-specific protease 2 (SENP2) can act as a suppressor in various types of cancer by regulating the stability of β-catenin to affect the Notch signaling pathway; however, it has a low expression level in CLL cells. In this study, we firstly used western blot analysis and RT-qPCR to detect the protein and mRNA expression levels of SENP2 in the peripheral blood of patients with CLL and healthy volunteers. Secondly, we overexpressed or knocked down the expression of SENP2 in CLL cells and then determined the cell invasive and chemotactic ability in a Transwell assay and chemotaxis assay. We examined the sensitivity of the cells to cytarabine and dexamethasone via a CCK-8 assay and determined the cell apoptotic condition and the expression of the Notch signaling pathway using flow cytometry and western blot analysis. The results demonstrated that the patients with CLL had relatively low expression levels of SENP2. The overexpression of SENP2 in the CLL cells decreased their invasive and proliferative ability, as well as their chemotactic response and enhanced their sensitivity to cytarabine and dexamethasone, while it promoted cell apoptosis. The silencing of SENP2 in the CLL cells generally produced the opposite results. We thus hypothesized that the overexpression of SENP2 downregulated β-catenin expression, thus inhibiting the Notch signaling pathway in CLL cells. Moreover, the nuclear factor (NF)-κB signaling pathway was also regulated by the overexpression of SENP2. On the whole, the findings of this study indicate tha SENP2 can act as a tumor suppressor in CLL cells, and may thus prove to be a novel target for CLL treatment in clinical practice.
Abstract. Fluorouracil (5-Fu) and 5-azacitidine (5-aza) are two types of nucleoside analog, which have been widely applied in the treatment of several types of cancer. However, the effect of these two types of drug on the proliferation and DNA methylation of cancer cells has not been compared in a single study. In the present study, in vitro cultured human gastric cancer cells (hGCCs) were treated with various concentrations of 5-Fu and 5-aza, and cell counting, MTT assay and methyl-sensitive amplified polymorphism were used to evaluate the resulting levels of proliferation and DNA methylation of hGCCs. The results revealed that the two drugs were able to inhibit the proliferation of hGCCs, but that the effect of 5-aza was weaker than that of 5-Fu. However, 5-aza decreased the level of DNA methylation in hGCCs, whereas 5-Fu did not alter DNA methylation. These results indicated that 5-Fu was able to more efficiently inhibit the proliferation of hGCCs than 5-aza, and that this difference may be due to differences in the anticancer mechanism of these two types of drug. IntroductionCancer, also known as malignant tumor, represents a significant threat to human health. Tumorigenesis occurs as a result of the activation of oncogenic pathways and/or inactivation of tumor suppressor pathways (1). Changes in the DNA sequence, including mutations, amplifications, gene rearrangements or deletions, were hypothesized to underlie tumorigenesis (2); however, aberrant epigenetic modifications also have a important role in cancer occurrence and progression. For example, DNA methylation, a type of epigenetic modification, was found to exhibit a distorted pattern in human cancer cells (3). Hypomethylation of intergenic regions and hypermethylation within the promoter regions of numerous CpG island-associated tumor suppressor genes has been observed in cancer cells (4,5). Hypomethylation of intergenic regions may result in the activation of transposable elements and instability of the genome in cancer cells (6), while hypermethylation of promoter regions may result in the silencing of tumor suppressor genes and uncontrolled cancer cell proliferation (7). Therefore, various types of DNA methyltransferase inhibitors have been used in cancer therapies (8). Fluorouracil (5-Fu) and 5-azacitidine (5-aza), two types of nucleoside analog, have been used to treat several types of cancer (8,9). However, the anticancer mechanisms underlying the effects of these two types of drug are distinct. Firstly, 5-aza is a type of DNA methyltransferase inhibitor, which is incorporated into DNA, leading to inhibition of DNA methylation and restoration of the expression of silenced tumor suppressor genes (10,11). By contrast, 5-Fu is a type of antimetabolite drug, which inhibits essential biosynthetic processes via incorporation into DNA and RNA, consequently inhibiting the normal function of these macromolecules in cancer cells (9). Although these two types of drug have been widely applied to treat various types of cancer, their effects on the prolifera...
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