Downregulation of RRM2 Attenuates Retroperitoneal Liposarcoma Progression via the Akt/mTOR/4EBP1 Pathway: Clinical, Biological, and Therapeutic Significance

Abstract

Sha Zhang,1 Liang Yan,1 Can Cui,2 Zhen Wang,1 Jianhui Wu,1 Ang Lv,1 Min Zhao,3 Bin Dong,4 Wenlong Zhang,5 Xiaoya Guan,1 Xiuyun Tian,1 Chunyi Hao1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 2Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 5Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaCorrespondence: Chunyi Hao; Xiuyun TianDepartment of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, People’s Republic of ChinaTel [phone]; [phone]Fax [phone]Email [email protected]; [email protected]: Retroperitoneal liposarcoma (RLPS) is a rare tumor with high recurrence rate. Ribonucleotide reductase small subunit M2 (RRM2) protein is essential for DNA synthesis and replication. Our previous study has demonstrated that RRM2 downregulation inhibited the proliferation of RLPS cells, but further association between RRM2 and RLPS and relevant mechanisms remains to be explored.Methods: RRM2 expression was evaluated in RLPS tumor tissues and cell lines by using real-time PCR and immunohistochemical analysis. The effect of RRM2 downregulation on cell proliferation, apoptosis, cell cycle, cell migration and invasion was tested by lentivirus. The effect of RRM2 inhibition on tumor growth in vivo was assessed by using patient-derived tumor xenograft (PDX) of RLPS and RRM2 inhibitor. The underlying mechanisms of RRM2 in RLPS were explored by protein microarray and Western blotting.Results: The results showed that RRM2 mRNA expression was higher in RLPS tissues than in normal fatty tissues (P< 0.001). RRM2 expression was higher in the dedifferentiated, myxoid/round cell, and pleomorphic subtypes (P=0.027), and it was also higher in the high-grade RLPS tissues compared to that in the low-grade RLPS tissues (P=0.004). There was no correlation between RRM2 expression and overall survival (OS) or disease-free survival (DFS) in this group of RLPS patients (P> 0.05). RRM2 downregulation inhibited cell proliferation, promoted cell apoptosis, facilitated cell cycle from G1 phase to S phase and inhibited cell migration and invasion. Inhibition of RRM2 suppressed tumor growth in NOD/SCID mice. Protein microarray and Western blot verification showed that activity of Akt/mammalian target of rapamycin/eukaryotic translation initiation factor 4E binding protein 1 (Akt/mTOR/4EBP1) pathway was downregulated along with RRM2 downregulation.Conclusion: RRM2 was overexpressed in RLPS tissues, and downregulation of RRM2 could inhibit RLPS progression. In addition, suppression of RRM2 is expected to be a promising treatment for RLPS patients.Keywords: retroperitoneal liposarcoma, ribonucleotide reductase small subunit M2, tumor progression, Akt/mTOR/4EBP1 pathway

Keywords

• retroperitoneal liposarcoma
• ribonucleotide reductase small subunit m2
• tumor progression
• akt/mtor/4ebp1 pathway