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Oncogenic Functions of Alternatively Spliced MDM2-ALT2 Isoform in Retroperitoneal Liposarcoma
Fernanda Costas C de Faria1, Safiya Khurshid2, Patricia Sarchet1
1The James Comprehensive Cancer Center, Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
International Journal of Molecular Sciences
|January 8, 2025
Summary
The alternatively spliced MDM2-ALT2 transcript may drive retroperitoneal liposarcoma (RPLPS) progression. This study found MDM2-ALT2 is upregulated in RPLPS and promotes cell proliferation and invasion via the AKT pathway.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Retroperitoneal liposarcoma (RPLPS) is a common soft tissue sarcoma (STS) with high recurrence rates.
- Well-differentiated and dedifferentiated subtypes (WDLPS/DDLPS) often feature MDM2 gene amplification.
- The role of alternatively spliced MDM2 transcripts in RPLPS remains under-investigated.
Purpose of the Study:
- To assess MDM2-ALT2 expression in RPLPS patient tissues.
- To investigate the in vitro biological functions of the MDM2-ALT2 isoform in dedifferentiated liposarcoma (DDLPS) cell lines.
Main Methods:
- Utilized BaseScope™ and quantitative PCR (qPCR) to measure MDM2-FL and MDM2-ALT2 expression in RPLPS tissues versus normal adjacent to tumor (NAT) tissues.
- Overexpressed MDM2-FL or MDM2-ALT2 in DDLPS cell lines to assess proliferation, migration, and invasion.
- Investigated the role of the AKT pathway by combining MDM2-ALT2 overexpression with AKT silencing.
Main Results:
- MDM2-Full Length (MDM2-FL) and MDM2-ALT2 were upregulated in RPLPS tissues compared to NAT.
- Overexpression of MDM2-FL or MDM2-ALT2 in DDLPS cells increased proliferation, migration, and invasion.
- Elevated protein levels of p-AKT, mTOR, p70S6K, MMP2, and cJun were observed with MDM2 overexpression.
- AKT inhibition counteracted MDM2-ALT2-induced increases in p-p70S6K and MMP2, reducing proliferation and migration.
Conclusions:
- MDM2-ALT2 is upregulated in RPLPS and contributes to tumor progression.
- MDM2-ALT2 promotes RPLPS cell proliferation and invasion, partly through the AKT/mTOR signaling pathway.
- MDM2-ALT2 represents a potential therapeutic target for RPLPS.
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