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

Abstract

Background: 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 patientderived 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 highgrade 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.

RRM2 Regulates Sensitivity to Sunitinib and PD‐1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway

“…Consistent with previous findings, [ 34 ] RRM2 overexpression promoted tumor growth and sunitinib resistance in renal cancer by regulating hypoxia and AKT pathway activation. Though it has been reported in previous studies that RRM2 activates the AKT pathway in cancer cells, [ 35 ] the underlying mechanisms have not been identified. In our study, we found that RRM2 activated AKT by increasing the protein levels of ANXA1, independent of the enzymatic activity of RRM2.…”

Expression and function of Siglec-15 in RLPS and its correlation with PD-L1: Bioinformatics Analysis and Clinicopathological Evidence

“…Currently, surgical treatment is the most effective treatment for RLPS [3]. However, treatment for recurrent and advanced sarcomas remains unsatisfactory [4][5][6], and multidisciplinary treatment is urgently needed for RLPS. DNA structure analysis suggests that different pathological types of sarcomas might have different immunological therapeutic potential [7,8].…”

Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

“…Besides, our studies also found that TYMS and RRM2 mRNA expression was higher in liposarcoma than normal adipose tissues and that TYMS overexpression was associated with poor prognosis in liposarcoma patients. While the previous study revealed TYMS downregulation inhibited STAT3 phosphorylation in liposarcoma cell and RRM2 downregulation inhibited the AKT signaling pathway ( 30 , 31 ). In the present study, RNA-seq and Western blot analysis showed that Apatinib might inhibit the RRM2/PI3K/AKT/mTOR signaling pathway and downregulate PD-L1 through the TYMS/STAT3 signaling pathway.…”