A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.

A mesenchymal tumor phenotype associates with immunotherapy resistance, although the mechanism is unclear. Here, we identified FBXO7 as a maintenance regulator of mesenchymal and immune evasion phenotypes of cancer cells. FBXO7 bound and stabilized SIX1 co-transcriptional regulator EYA2, stimulating mesenchymal gene expression and suppressing IFNα/ß, chemokines CXCL9/10, and antigen presentation machinery, driven by AXL extracellular ligand GAS6. Ubiquitin ligase SCFFBXW7 antagonized this pathway by promoting EYA2 degradation. Targeting EYA2 Tyr phosphatase activity decreased mesenchymal phenotypes and enhanced cancer cell immunogenicity, resulting in attenuated tumor growth and metastasis, increased infiltration of cytotoxic T and NK cells, and enhanced anti-PD-1 therapy response in mouse tumor models. FBXO7 expression correlated with mesenchymal and immune-suppressive signatures in patients with cancer. An FBXO7-immune gene signature predicted immunotherapy responses. Collectively, the FBXO7/EYA2-SCFFBXW7 axis maintains mesenchymal and immune evasion phenotypes of cancer cells, providing rationale to evaluate FBXO7/EYA2 inhibitors in combination with immune-based therapies to enhance onco-immunotherapy responses.

The surface modification of long carbon fiber reinforced polyether ether ketone with bioactive composite hydrogel for effective osteogenicity.

Long carbon fiber reinforced polyether ether ketone (LCFRPEEK) is fabricated using a three-dimensional (3D) needle-punched method in our previous work, which is considered as a potential orthopedic implant due to its high mechanical strength and isotropic properties, as well as having an elastic modulus similar to human cortical bone. However, the LCFRPEEK has inferior integration with bone tissue, limiting its clinical application. Thus, a facile surface modification method, using gelatin methacrylate/polyacrylamide composite hydrogel coating (GelMA/PAAM) loading with dexamethasone (Dex) on our newly-developed LCFRPEEK composite via concentrated sulfuric acid sulfonating and ultraviolet (UV) irradiation grafting methods, has been developed to tackle the problem. The results demonstrate that the GelMA/PAAM/Dex coating modified sulfonated LCFRPEEK (SCP/GP/Dex) has a hydrophilicity surface, a long-term Dex release capability and forms more bone-like apatite nodules in SBF. The SCP/GP/Dex also displays enhanced cytocompatibility and osteogenic differentiation in terms of rat bone marrow mesenchymal stem cells (rBMSCs) responses in vitro assay. The in vivo rat cranial defect assay confirms that SCP/GP/Dex boosts bone regeneration/osseointegration, which significantly improves osteogenic fixation between the implant and bone tissue. Therefore, the newly-developed LCFRPEEK modified via GelMA/PAAM/Dex bioactive coating exhibits improved biocompatibility and osteogenic integration capability, which has the basis for an orthopedic implant for clinical application.

FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells.

Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.

Knockdown of Kif20a inhibits growth of tumors in soft tissue sarcoma in vitro and in vivo.

Kif20a (Kinesin Family Member 20A), plays a role in cell mitosis, cell migration and intracellular transport. Numerous studies have demonstrated that Kif20a is abnormally highly expressed in a variety of tumors and shows poor prognosis. Soft tissue sarcoma (STS) represents a group of malignant tumors with poor prognosis. The role of Kif20a in STSs has not been systematically studied. In the present study, bioinformatics analysis, in vitro and in vivo experiments were conducted to investigate the function of Kif20a in STSs. In bioinformatics analysis higher KIf20a expression indicated a poor prognosis. Functional enrichment analysis indicated that Kif20a may be related to cell cycle, p53 and other signaling pathways. In vitro experiments showed that after the down-regulation of Kif20a, cell proliferation, migration and invasion were decreased, while apoptosis was increased. In vivo experiments revealed that Kif20a affected the proliferation of tumors in tumor-bearing mice. In summary, our findings revealed that Kif20a performs an important role in STS, indicating that it is a potential prognostic biomarker and potentially representing a therapeutic target for the disease.

Integrative Clustering Reveals a Novel Subtype of Soft Tissue Sarcoma With Poor Prognosis.

BACKGROUND: Soft tissue sarcomas (STSs) are heterogeneous at the clinical and molecular level and need to be further sub-clustered for treatment and prognosis. MATERIALS AND METHODS: STSs were sub-clustered based on RNAseq and miRNAseq data extracted from The Cancer Genome Atlas (TCGA) through the combined process of similarity network fusion (SNF) and consensus clustering (CC). The expression and clinical characteristics of each sub-cluster were analyzed. The genes differentially expressed (lncRNAs, miRNAs, and mRNAs) between the poor prognosis and good prognosis clusters were used to construct a competing endogenous RNA (ceRNA) network. Functional enrichment analysis was conducted and a hub network was extracted from the constructed ceRNA network. RESULTS: A total of 247 STSs were classified into three optimal sub-clusters, and patients in cluster 2 (C2) had a significantly lower rate of survival. A ceRNA network with 91 nodes and 167 edges was constructed according to the hypothesis of ceRNA. Functional enrichment analysis revealed that the network was mainly associated with organism development functions. Moreover, LncRNA (KCNQ1OT1)-miRNA (has-miR-29c-3p)-mRNA (JARID2, CDK8, DNMT3A, TET1)-competing endogenous gene pairs were identified as hub networks of the ceRNA network, in which each component showed survival significance. CONCLUSION: Integrative clustering analysis revealed that the STSs could be clustered into three sub-clusters. The ceRNA network, especially the subnetwork LncRNA (KCNQ1OT1)-miRNA (has-miR-29c-3p)-mRNA (JARID2, CDK8, DNMT3A, TET1) was a promising therapeutic target for the STS sub-cluster associated with a poor prognosis.

Co-expression Network Analysis Identifies Four Hub Genes Associated With Prognosis in Soft Tissue Sarcoma.

Background: Soft tissue sarcomas (STS) are heterogeneous tumors derived from mesenchymal cells that differentiate into soft tissues. The prognosis of patients who present with an STS is influenced by the regulation of a complex gene network. Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules associated with STS (Samples = 156). Results: Among the 11 modules identified, the black and blue modules were highly correlated with STS. However, using preservation analysis, the black module demonstrated low preservation, therefore the blue module was chosen as the module of interest. Furthermore, a total of 20 network hub genes were identified in the blue module, 12 of which were also hub nodes in the protein-protein interaction network of the module genes. Following additional verification, 4 of 12 genes (RRM2, BUB1B, CENPF, and KIF20A) demonstrated poorer overall survival and disease-free survival rate in the test datasets. In addition, gene set enrichment analysis (GSEA) demonstrated that samples with a high level of blue module eigengene (ME) were enriched in cell cycle and metabolism associated signaling pathways. Conclusion: In summary, co-expression network analysis identified four hub genes associated with prognosis for STS, which may diminish the prognosis by influencing cell cycle and metabolism associated signaling pathways.

Interleukin-35 suppresses antitumor activity of circulating CD8+ T cells in osteosarcoma patients.

Purpose/Aim of the study: Interleukin (IL)-35 is a newly identified IL-12 cytokine family member and reveals immunosuppressive activity to CD8+ T cells in inflammation, infectious diseases, and cancers. However, little is known regarding IL-35 function in osteosarcoma. Thus, the aim of the current study was to investigate the regulatory function of IL-35 to CD8+ T cells in osteosarcoma. Materials and methods: Thirty-five osteosarcoma patients and 20 healthy individuals were enrolled. Serum CD4+CD25+CD127dim/- regulatory T cells (Tregs) and CD8+ T cells were purified. IL-35 concentration in serum and cultured supernatants was measured by enzyme-linked immunosorbent assay. Osteosarcoma cell line MG-63 cells and CD8+ T cells were stimulated with recombinant IL-35 in vitro, and modulatory function of IL-35 on these cells was assessed by investigation of cellular proliferation, cell cycle, apoptosis, and cytokine production. Results: Serum IL-35 and Treg-secreting IL-35 were significantly elevated in osteosarcoma patients. IL-35 stimulation did not affect proliferation, apoptosis, or cell cycle of MG-63 cells. Purified peripheral CD8+ T cells from osteosarcoma patients revealed dysfunctional property, which presented as decreased mRNA expressions for perforin, granzyme B, and granulysin, as well as reduced cytolytic (direct lysis of target MG-63 cells) and noncytolytic (interferon-γ and tumor necrosis factor-α production) function in coculture systems. Moreover, IL-35 stimulation further diminished cytolytic and noncytolytic activity of CD8+ T cells from osteosarcoma patients. Conclusions: The current data indicated that IL-35 contributed to CD8+ T-cell dysfunction and limited antitumor immune response in osteosarcoma.

Using co-axial electrospray deposition to eliminate burst release of simvastatin from microparticles and to enhance induced osteogenesis.

Microparticles (MPs) exhibit fast dissolution, characterized by a burst drug release pattern. In the present work, we prepared core-shell MPs of simvastatin (SIM) and zein with chitosan (CS) and nano-hydroxyapatite (nHA) as a drug carrier using the coaxial electrospray deposition method. The morphology, formation and in vitro osteogenic differentiation of these MPs were studied. The synthetic MPs have a diameter of about 1 µm and they are composed of non-toxic natural materials. They provide an effective way to enable long-term sustained-release activity, which is controlled by their double layer structures. The CS-nHA/zein-SIM MPs presented a low initial burst release (approximately 35-47%) within the first 24 h of application followed by the sustained release for at least 4 weeks. In vitro cell culture experiments were performed and the results revealed that the CS-nHA/zein-SIM core-shell MPs were beneficial to the adhesion, proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The CS-nHA/zein-SIM MPs with a low SIM concentration were beneficial to cell proliferation and promotion of osteogenic differentiation.

Paclitaxel and etoposide-loaded Poly (lactic-co-glycolic acid) microspheres fabricated by coaxial electrospraying for dual drug delivery.

In this study, we fabricated paclitaxel (PTX) and etoposide (ETP) loaded Poly (lactic-co-glycolic acid) (PLGA) microspheres with core-shell structures and particle sizes ranging from 1 to 4 µm by coaxial electrospraying. The microspheres were analyzed by scanning electron microscopy (SEM), transmission electron microscopy (TEM). The drug loading rate and entrapment efficiency of the microspheres were detected by high performance liquid chromatograph (HPLC). Moreover, the drug release profiles and degradation of drug-loaded PLGA microspheres in vitro were investigated, respectively. The distinct layered structure that existed in the manufactured core-shell microspheres can be observed by TEM. The in vitro release profiles indicated that the PLGA/PTX + ETP (PLGA/PE) microspheres exhibited the controlled release of two drugs in a sequential manner. Cell Counting Kit-8 was used to detect the toxic and side effects of the microspheres on bone tumor cells. PTX and ETP for combination drug therapy loaded microspheres had more cytotoxic effect on saos-2 osteosarcoma cells than the individual drugs. In conclusion, core-shell PLGA microspheres by electrospraying for combination drug therapy is promising for medicine applications, the PLGA/PE microspheres have some potential for osteosarcoma treatment.

Potential of rhBMP-2 and dexamethasone-loaded Zein/PLLA scaffolds for enhanced in vitro osteogenesis of mesenchymal stem cells.

Nanofibers fabricated by electrospinning simulate the extracellular matrix of bone cells and so researchers have taken a keen interest in them for regenerating bone tissue. The aim of this study was to fabricate ideal Zein/PLLA nanofibers by coaxial electrospinning and to load them with bone morphogenetic protein 2 (BMP-2) and dexamethasone (DEX) for dual controlled-release for bone tissue engineering applications. Morphology, surface hydrophilicity and core-shell construction were analyzed by environmental scanning electron microscopy (SEM), water contact angle and transmission electron microscopy (TEM). The properties of the scaffolds were studied in terms of the viability, morphology and osteogenic differentiation of mesenchymal stem cells (MSCs) that had been cultured on nanofiber mats of the Zein/PLLA and were determined using SEM, CCK-8 assay, quantitative ALP staining analysis, quantitative mineral deposition using Alizarin red staining (ARS), immunofluorescence staining and western blot analysis of osteogenic proteins. In vitro studies demonstrated that the biological activity of DEX and BMP-2 was retained in the dual-drug-loaded nanofiber scaffolds. A large quantity of DEX was released in the first three days, while the release of BMP-2 lasted for more than 21 days. In vitro osteogenesis studies showed that the drug-loaded nanofiber scaffolds induced osteogenic differentiation. Furthermore, the dual controlled-release of BMP-2 and DEX enhanced the osteogenic differentiation of MSCs resulting from synergistic effects. Therefore, Zein/PLLA nanofiber scaffolds loaded with BMP-2 and DEX have great potential in bone tissue engineering applications.

Shockwaves Inhibit Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Association with Adenosine and A2B Receptors.

Extracorporeal shockwave therapy (ESWT) has emerged as the important choice for the treatment of many orthopedic disorders. Our previous mechanistic studies suggest that ESWT promoted osteogenesis of human mesenchymal stem cells (hMSCs) through mechanisms that involve adenosine 5'-triphosphate (ATP) release. In this study, we investigated the effect of ESWT on chondrogenesis of hMSCs. We demonstrate that ESWT treatment caused a significant release of adenosine from hMSCs; ESWT treatment increased the levels of A2B receptor (A2BR) in hMSCs under 3-D culture conditions. ESWT, exogenous adenosine and specialized A2BR agonist suppressed hMSC chondrogenic differentiation through downregulating the expressions of aggrecan (ACAN), Collagen Type I alpha 2(COL1A2), Collagen Type II alpha 1(COL2A1), Sex-Determining Region YBox 9 (SOX9) and Sex-Determining Region YBox 6 (SOX6). Selective A2BR antagonists induced chondrogenic differentiation of hMSCs. This study indicated that shockwave therapy inhibits hMSC chondrogenic differentiation through or partially through regulation of adenosine release and activation of A2B receptor under 3-D culture conditions.

Prognostic value of programmed death-ligand 1 in sarcoma: a meta-analysis.

BACKGROUND: The prognostic role of programmed death-ligand 1 (PD-L1) in sarcoma remains controversial. We performed a meta-analysis so as to investigate the impact of PD-L1 on clinicopathlogical findings and survival outcomes in sarcoma. MATERIALS AND METHODS: A comprehensive search in PubMed, Embase and the Cochrane Library was conducted for relevant studies. The odds ratios or hazard ratios, at 95% confidence intervals were used as measures for investigation of the correlation between PD-L1 expression and clinicopathlogical features or survival outcomes. RESULTS: Fourteen eligible studies comprising 868 patients were selected for analysis. Pooled hazard ratios indicated that the association of PD-L1 expression with overall survival in bone sarcoma (osteosarcoma and chondrosarcoma) patients was statistically significant (1.987, 95% CI: 1.224-3.224, p = 0.005), as was its association with event-free survival in bone and soft-tissue sarcoma patients (3.868, 95% CI: 2.298-6.511, p = 0.000). Additionally, the expression of PD-L1 was positively correlated with the infiltration of programmed death 1 (PD-1) positive T-lymphocytes (OR: 4.012, 95% CI: 2.391-6.733, p = 0.000). CONCLUSIONS: Our meta-analysis indicated that high PD-L1 expression is likely to be a negative factor for patients with sarcomas and that it predicts worse survival outcomes.

Patellar tendon ossification after retrograde intramedullary nailing for distal femoral shaft fracture: A case report and review of the literature.

RATIONALE: Retrograde femoral nailing was one of the most important treatment means for distal femoral shaft fracture. However, studies regarding heterotopic ossification of the patellar tendon after retrograde intramedullary nailing for distal femoral shaft fracture are limited. We herein present a rare complication, namely heterotopic ossification of the patellar tendon, after retrograde intramedullary nailing for displaced femoral shaft fracture. PATIENT CONCERNS: We present a case of 25-year-old male with displaced femoral shaft fracture who was treated by retrograde intramedullary nailing. DIAGNOSES: During the period of follow-up, the patient developed symptomatic heterotopic ossification of the patellar tendon with extensively hard ossification area. INTERVENTIONS: Open surgery was recommended, but the patient has refused further treatment. OUTCOMES: The patient resulted in pain and restricted the range of motion of the affected knee. LESSONS: This case stresses the importance of longer-term follow-up and further attention into the possibility of heterotopic ossification of the patellar tendon.

Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate.

BACKGROUND: Osteosarcoma is the most prevalent primary malignant bone tumor, but treatment is difficult and prognosis remains poor. Recently, large-dose chemotherapy has been shown to improve outcome but this approach can cause many side effects. Minimizing the dose of chemotherapeutic drugs and optimizing their curative effects is a current goal in the management of osteosarcoma patients. METHODS: In our study, trypan blue dye exclusion assay was performed to investigate the optimal conditions for the sensitization of osteosarcoma U2OS cells. Cellular uptake of the fluorophores Lucifer Yellow CH dilithium salt and Calcein was measured by qualitative and quantitative methods. Human MTX ELISA Kit and MTT assay were used to assess the outcome for osteosarcoma U2OS cells in the present of shock wave and methotrexate. To explore the mechanism, P2X7 receptor in U2OS cells was detected by immunofluorescence and the extracellular ATP levels was detected by ATP assay kit. All data were analyzed using SPSS17.0 statistical software. Comparisons were made with t test between two groups. RESULTS: Treatment of human osteosarcoma U2OS cells with up to 450 shock wave pulses at 7 kV or up to 200 shock wave pulses at 14 kV had little effect on cell viability. However, this shock wave treatment significantly promoted the uptake of Calcein and Lucifer Yellow CH by osteosarcoma U2OS cells. Importantly, shock wave treatment also significantly enhanced the uptake of the chemotherapy drug methotrexate and increased the rate of methotrexate-induced apoptosis. We found that shock wave treatment increased the extracellular concentration of ATP and that KN62, an inhibitor of P2X7 receptor reduced the capacity methotrexate-induced apoptosis. CONCLUSIONS: Our results suggest that shock wave treatment promotes methotrexate-induced apoptosis by altering cell membrane permeability in a P2X7 receptor-dependent manner. Shock wave treatment may thus represent a possible adjuvant therapy for osteosarcoma.

A polysaccharide from the leaves of Aralia elata induces apoptosis in U-2 OS cells via mitochondrial-dependent pathway.

In the present study, we isolated and characterized one purified polysaccharide (AEP-1) from the leaves of Aralia elata, and investigated its effect on human osteosarcoma (OS) U-2 OS cell line and analyzed its mechanism. MTT assays showed that AEP-1 markedly inhibited the growth of U-2 OS cells in a dose- and time-dependent fashion, suggesting a cytotoxic effect. The AEP-1 also dose-dependently induced DNA fragmentation and caused apoptotic death in U-2 OS cells. The event of apoptosis was accompanied by increased ratio of Bax/Bcl-2, depolarization of mitochondrial membrane potential (Δym) and the release of cytochrome c from mitochondria into the cytoplasm. Moreover, AEP-1 treatment triggered the activation of caspase-9 and caspase-3, as well as the cleavage of poly (ADP-ribose) polymerase (PAPR) in U-2 OS cells. All these results suggests that the induction of apoptosis by AEP-1 in U-2 OS cells occurs through the mitochondria-dependent pathway and AEP-1 may be useful in treating OS and improving cancer chemotherapy.

Death Due to Intra-aortic Migration of Kirschner Wire From the Clavicle: A Case Report and Review of the Literature.

Migration of orthopedic fixation wires into the ascending aorta though a rare occurrence can have devastating consequences. Therefore, prompt recognition, with immediate and cautious retrieval of the implant is paramount in averting these complications.We present a case of a 5-year-old boy with the intra-aortic migration of a K-wire used for the treatment of a right clavicle fracture. He was transferred to us with a history of syncope, chest pain, and shortness of breath 7 days after K-wire placement, which was performed at another hospital. On CT scan, the wire was found to be partially inside the ascending aorta, which was associated with massive hemopericardium and cardiac tamponade. The patient was taken up for emergency surgery for the removal K-wire and for the management of cardiac temponade. However, the patient developed cardiac arrest during the induction of intravenous anesthesia and endotracheal intubation. The K-wire was retrieved from the thorax via thoracotomy. However, the patient died 10 days after the surgery.As the migration of wires and pins during orthopedic surgery can cause potentially fatal complications, these should be used very cautiously, especially for percutaneous treatment of shoulder girdle fractures. The patients with such implants should be followed frequently, both clinically and radiographically. If migration occurs, the patient should be closely monitored for emergent complications and the K-wire should be extracted immediately.

Posterior dislocation of the hip with bilateral femoral fractures: An unusual combination.

Posterior hip dislocation with concomitant femoral fracture is very rare. Here, we report a rare case of a 43-year-old man who was injured in a car accident. The patient sustained right posterior hip dislocation with concomitant right acetabular transverse and posterior wall fracture, ipsilateral femoral shaft fracture, and contralateral proximal femoral fracture (AO type 31-A3). Closed reduction of the hip was attempted, but failed. The acetabular fracture and posterior hip dislocation were reduced and acetabular fracture was fixed using plates through the Kocher-Langenbeck approach. The ipsilateral femoral fracture was treated with closed reduction and intramedullary nailing. The contralateral femoral fracture was treated with closed reduction and Gamma 3 nailing. Postoperative X-rays revealed reduction of the fractures. The patient achieved bone union and recovered function of the hip 4 months after surgery.

A novel technique to prevent guide wire related complications while inserting the 4.0 mm cannulated screws.

BACKGROUND: Cannulated screws (4.0 mm) provide inter-fragmentary compression and stability to fractures. A guide wire is used to define the screw trajectory and hold the fracture fragment while the screw is being inserted. The cannulated shaft typically accommodates a 1.25 mm guide pin. Since the guide pin is very slender and undergoes elastic deformation during insertion, there is a high probability of pin breakage. METHODS: The authors have devised a new way to place the 4.0 mm cannulated screws in a manner that prevents the intraoperative complication of guide wire breakage. For this technique, predrilling was achieved using a 2.0 mm K-wire which was subsequently replaced with a 1.25 mm guide pin under the protection of sleeve. 4.0 mm cannulated screws were then inserted into a defined trajectory over the guide pin. RESULTS: Using the technique, over 20 patients were managed in our department over a period of two years without any complications. CONCLUSION: We have observed that patients treated with this method experience short operation time, combined with good clinical outcome and we recommend its use in cases where cannulated screw use is warranted.

PP2A-B55ß antagonizes cyclin E1 proteolysis and promotes its dysregulation in cancer.

Cyclin E1 regulates the initiation of S-phase in cellular division. However, in many cancers, cyclin E1 is aberrantly overexpressed and this molecular phenotype correlates with increased tumor aggressiveness and poor patient survival. The molecular cause(s) of cyclin E1 abnormalities in cancers is poorly understood. Here, we show that cyclin E1 overexpression in cancer is promoted by dysregulation of the protein phosphatase PP2A-B55ß. PP2A-B55ß targets the N- and C-terminal phosphodegrons of cyclin E1 for dephosphorylation, thus protecting it from degradation mediated by the SCF(Fbxw7) ubiquitin ligase. Augmented B55ß expression stabilizes cyclin E1 and promotes its overexpression in cancer-derived cell lines and breast tumors. Conversely, B55ß ablation enforces the degradation of cyclin E1 and inhibits cancer cell proliferation in vitro and tumor formation in vivo. Therefore, PP2A-B55ß promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers.