Abstract
Approximately 90% of well-differentiated/de-differentiated liposarcomas (WDLPS/DDLPS), the most common LPS subtype, have chromosomal amplification at 12q13-q22. Many protein-coding genes in the region, such as MDM2 and , have been studied as potential therapeutic targets for LPS treatment, with minimal success. In the amplified region near the MDM2 gene, our single nucleotide polymorphism (SNP) array analysis of 75 LPS samples identified frequent amplification of miR-26a-2. Besides being in the amplicon, miR-26a-2 was overexpressed significantly in WDLPS/DDLPS (P<0.001), as well as in myxoid/round cell LPS (MRC) (P<0.05). Furthermore, Kaplan–Meier survival analysis showed that overexpression of miR-26a-2 significantly correlated with poor patient survival in both types of LPS (P<0.05 for WDLPS/DDLPS; P<0.001 for MRC). Based on these findings, we hypothesized that miR-26a-2 has an important role in LPS tumorigenesis, regardless of LPS subtypes. Overexpression of miR-26a-2 in three LPS cell lines (SW872, LPS141 and LP6) enhanced the growth and survival of these cells, including faster cell proliferation and migration, enhanced clonogenicity, suppressed adipocyte differentiation and/or resistance to apoptosis. Inhibition of miR-26a-2 in LPS cells using anti-miR-26a-2 resulted in the opposite responses. To explain further the effect of miR-26a-2 overexpression in LPS cells, we performed in silico analysis and identified 93 candidate targets of miR-26a-2. Among these genes, RCBTB1 (regulator of chromosome condensation and BTB domain-containing protein 1) is located at 13q12.3-q14.3, a region of recurrent loss of heterozygosity (LOH) in LPS. Indeed, either overexpression or inhibition of RCBTB1 made LPS cells more susceptible or resistant to apoptosis, respectively. In conclusion, our study for the first time reveals the contribution of miR-26a-2 to LPS tumorigenesis, partly through inhibiting RCBTB1, suggesting that miR-26a-2 is a novel therapeutic target for human LPS.
Highlights
Human liposarcoma (LPS) is the most common soft-tissue sarcoma, comprising 24–45% of the total soft-tissue sarcomas.1,2 Surgical resection can effectively manage primary local disease, but metastatic disease cannot be cured either by surgery, chemotherapy or radiotherapy
When we considered only WDLPS/DDLPS, the percentage of copy number (CN) gains surged to 83% (35 samples)
In this study, we analyzed the genomic aberrations of 75 human LPS and identified several new recurrent regions of genomic abnormalities, most notably the recurrent loss of heterozygosity (LOH) in 13q12.3-q14.3
Summary
Human liposarcoma (LPS) is the most common soft-tissue sarcoma, comprising 24–45% of the total soft-tissue sarcomas. Surgical resection can effectively manage primary local disease, but metastatic disease cannot be cured either by surgery, chemotherapy or radiotherapy. Human liposarcoma (LPS) is the most common soft-tissue sarcoma, comprising 24–45% of the total soft-tissue sarcomas.. Surgical resection can effectively manage primary local disease, but metastatic disease cannot be cured either by surgery, chemotherapy or radiotherapy. LPS is grouped in three major subtypes depending on their histopathological characteristics: (1) Well-differentiated/ de-differentiated (WDLPS/DDLPS), (2) myxoid/round cell LPS (MRC) and (3) pleomorphic LPS. WDLPS/DDLPS is the most common subtype and is characterized by chromosomal amplification at 12q13-q22, which contains the MDM2 and CDK4 genes in 90% of the cases. Laboratory investigators have focused on blocking the function of these amplified genes with Nutlin 3a and several novel compounds, respectively.. Laboratory investigators have focused on blocking the function of these amplified genes with Nutlin 3a and several novel compounds, respectively.1–4 To date, these approaches have shown disappointing clinical outcomes Laboratory investigators have focused on blocking the function of these amplified genes with Nutlin 3a and several novel compounds, respectively. To date, these approaches have shown disappointing clinical outcomes
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