de Faria Fernanda Costas C, Khurshid Safiya, Sarchet Patricia, Tahara Sayumi, Casadei Lucia, Grignol Valerie, Karna Roma, Rentsch Sydney, Sp Nipin, Beane Joal D, Mazzoccoli Luciano, Montes Matias, Nigita Giovanni, Sharick Joe T, Leight Jennifer L, Calore Federica, Chandler Dawn S, Pollock Raphael E
The James Comprehensive Cancer Center, Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Int J Mol Sci. 2024 Dec 17;25(24):13516. doi: 10.3390/ijms252413516.
Retroperitoneal liposarcoma (RPLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS). Complete surgical resection remains the mainstay treatment, while the high rate of locoregional recurrence constitutes the predominant cause of mortality. Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are the most frequent subtypes of RPLPS and present amplified MDM2 gene as a hallmark. However, there are few reports evaluating the role of alternatively spliced MDM2 transcripts in RPLPS. In this study, we assessed MDM2-ALT2 expression levels in a cohort of RPLPS patients and evaluated the biological functions of the MDM2-ALT2 isoform in vitro in DDLPS cell lines. Using BaseScope™ and qPCR, we demonstrated that MDM2-Full Length (MDM2-FL) and MDM2-ALT2 expression levels were upregulated in RPLPS patient-derived tissue samples compared to normal adjacent to tumor tissue (NAT). DDLPS cells overexpressing MDM2-FL or MDM2-ALT2 had higher proliferation rates and increased migration and invasion capacities, as well as increased protein levels of p-AKT, mTOR, p70S6K, MMP2, and cJun. Simultaneous overexpression of MDM2-ALT2 and AKT silencing showed that AKT inhibition impaired p-p70S6K and MMP2 protein increased levels and led to significantly decreased proliferation and migration rates compared to cells overexpressing MDM2-ALT2 only. Taken together, our data suggest that MDM2-ALT2 may promote RPLPS progression.
腹膜后脂肪肉瘤（RPLPS）是软组织肉瘤（STS）最常见的组织学亚型之一。完整的手术切除仍然是主要的治疗方法，而局部区域复发率高是主要的死亡原因。高分化（WDLPS）和去分化（DDLPS）脂肪肉瘤是RPLPS最常见的亚型，其特征是MDM2基因扩增。然而，很少有报道评估可变剪接的MDM2转录本在RPLPS中的作用。在本研究中，我们评估了一组RPLPS患者中MDM2-ALT2的表达水平，并在体外评估了DDLPS细胞系中MDM2-ALT2异构体的生物学功能。使用BaseScope™和qPCR，我们证明与肿瘤旁正常组织（NAT）相比，RPLPS患者来源的组织样本中MDM2全长（MDM2-FL）和MDM2-ALT2的表达水平上调。过表达MDM2-FL或MDM2-ALT2的DDLPS细胞具有更高的增殖率，迁移和侵袭能力增强，同时p-AKT、mTOR、p70S6K、MMP2和cJun的蛋白水平也增加。MDM2-ALT2和AKT沉默的同时过表达表明，与仅过表达MDM2-ALT2的细胞相比，AKT抑制会损害p-p70S6K和MMP2蛋白水平的增加，并导致增殖和迁移率显著降低。综上所述，我们的数据表明MDM2-ALT2可能促进RPLPS的进展。
