Study of miR-26a-2 gene as a therapeutic target of human liposarcoma
Despite its high occurrence, human liposarcoma (LPS) lacks effective treatment options except surgical resection of localized tumor mass. Progressive disease may have a temporary response to chemotherapy. Approximately 90% of well-differentiated/de-differentiated LPS (WDLPS/DDLPS), the most common LPS subtype, have chromosomal amplification at 12q13-q15. Many protein-coding genes in the region, such as MDM2 and CDK4, have been studied as potential therapeutic targets for LPS treatment with minimal success to date. Within this amplicon near to the MDM2 gene, our preliminary data showed that a microRNA (miRNA), miR-26a-2, was amplified.
miRNAs are short, non-coding RNAs that can provide the coordinated regulation of multiple genes. When they become dysregulated, they can enhance development and/or progression of cancers. Besides being in the amplicon, we found that miR-26a-2 is overexpressed significantly in WDLPS/DDLPS. Surprisingly, we also noted that overexpression of miR-26a-2 occurred in myxoid/round cell LPS (MRC) without apparent amplification of the gene. In our further preliminary data, Kaplan-Meier survival analysis showed that overexpression of miR-26a-2 significantly correlated with poor patient survival in both types of LPS.
Based on these findings, we hypothesize that miR-26a-2 plays an important role in LPS tumorigenesis, regardless of LPS subtypes. To understand the role of miR-26a-2 in LPS, we propose the following Specific Aims: (1) To investigate the in vitro effect of miR-26a-2 on the proliferation and survival of LPS cells; (2) To identify novel, LPS-specific target proteins of miR-26a-2; (3) To validate the importance of miR-26a-2 in the preclinical setting.
In conclusion, our study will reveal the contribution that miR-26a-2 makes to LPS tumorigenesis. Better understanding of the dysfunction of miR-26a-2 in LPS will provide the knowledge to develop a new therapeutic approach to attack this pernicious cancer.