CCNDBP1, a Prognostic Marker Regulated by DNA Methylation, Inhibits Aggressive Behavior in Dedifferentiated Liposarcoma via Repressing Epithelial Mesenchymal Transition.

Lingge Yang,Shiqi Chen,Wangjun Yan,Wei Sun,Zhiqiang Wu,Yong Chen,Yan Li,Chunmeng Wang,Peng Luo

doi:10.3389/fonc.2021.687012

Abstract

The present study aimed to explore the prognostic value, function, and mechanism of CCNDBP1 in dedifferentiated liposarcoma (DDL). Immunohistochemistry staining was used to analyze the protein expression of CCNDBP1 in tissue specimens. After silencing CCNDBP1 in LPS853 and overexpressing CCNDBP1 in LPS510, CCK-8, clone formation, transwell migration, and invasion assays were used to detect cell proliferation, migration, and invasion ability. CCNDBP1-induced cell apoptosis was analyzed by flow cytometry. The altered expression of epithelial-mesenchymal transition (EMT)-related proteins were detected by Western blot. The methylation, gene expression, and clinical data of 58 samples with DDL were analyzed using the cancer genome atlas (TCGA) database. Low expression of CCNDBP1 was associated with a poor prognosis of patients with DDL and was considered an independent prognostic factor of the progression-free survival (PFS). CCNDBP1 significantly inhibited the clone formation, proliferation, migration, and invasion of cancer cells in vitro and promoted cancer cell apoptosis. CCNDBP1 could repress the pathological EMT, thereby inhibiting the malignant behaviors of DDL cells. The high degree of DNA methylation sites cg05194114 and cg22184989 could decrease the expression of CCNDBP1 and worsen the prognosis of DDL patients. This is the first study reporting that CCNDBP1 is a tumor suppressor gene of DDL and putative prognostic marker in DDL patients. CCNDBP1 might inhibit the ability of cell proliferation and invasion by repressing pathological EMT, and the expression of CCNDBP1 could be regulated by DNA methylation in DDL.

Highlights

Liposarcoma is a mesenchymal malignancy with distinct tissue diversity, consisting of adipocytes with different degrees of differentiation and heteromorphosis
After high-throughput sequencing, the differential genes were screened with |log2 fold change (FC)| > 1, and a total of 5,037 genes with statistically significant expression differences (P < 0.05) were identified, among which, 162 genes were upregulated, and 4,875 genes were downregulated in dedifferentiated liposarcoma (DDL) compared with Well-differentiated liposarcoma (WDL) (Figure 1A)
The results indicated that the expression of E-cadherin, ZO-1, and Claudin-1 proteins related with epithelial cell structures and tight junctions was downregulated, while the expression of N-cadherin, Vimentin, and ASMA, markers related to the mesenchymal cell status was upregulated

Summary

Introduction

Liposarcoma is a mesenchymal malignancy with distinct tissue diversity, consisting of adipocytes with different degrees of differentiation and heteromorphosis. Well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL) are the most common types of liposarcoma, accounting for about 40%–45% of the liposarcomas [1]. The invasion ability of WDL is poor; it does not appear metastatic but has the tendency of recurrence [2]. It could be dedifferentiated and converted into DDL, obtaining a stronger invasive ability, rapid local recurrence, and distant metastasis, which occurs in about 10% of WDLs [3, 4]. DDL shares the amplification of MDM2 and CDK4 with WDL, while additional abnormalities are frequently found in DDL than WDL, including the amplification of JUN, MAP3K5, TERT, and CPM, and deletion of ATRX, ATM, CHEK1, ABTB16, PPP2R1B, and EI24 [5]

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Discussion

Conclusion