Chondrosarcoma Cells Research Articles

Growth Inhibition and Induction of Innate Immune Signaling of Chondrosarcomas with Epigenetic Inhibitors.

Chondrosarcomas are inherently resistant to chemotherapy and radiotherapy, pointing to an unmet need for new treatment options. Immune checkpoint inhibitors, which have shown remarkable promise in multiple solid cancer types, have limited efficacy in chondrosarcomas. Mutations in IDH1/2 genes, which result in progressive increases in DNA and histone methylation, are observed in 50% of conventional chondrosarcomas, suggesting that epigenetic dysregulation represents a potential barrier for tumor progression and target for therapeutic intervention. Here, we demonstrated that combined treatment of FDA-approved inhibitors of DNA methyltransferases (DNMTs) 5-aza-2'-deoxycytidine (5-aza), and histone deacetylases (HDACs) suberanilohydroxamic acid (SAHA) impaired the proliferation of chondrosarcoma cell lines in vitro and in xenograft studies. Transcriptomic analysis reveals that chondrosarcoma cells treated with 5-aza and SAHA markedly elevated the expression of IFN-stimulated genes including PD-L1, indicating that these epigenetic drugs induced a potent innate immune response. We demonstrated that 5-aza and SAHA resulted in both genomic and epigenomic instability, as shown by elevated DNA damage response and derepression of retrotransposons, respectively, which in turn activated pattern recognition receptors (PRRs) and the downstream IFN signaling pathways. Importantly, the cytotoxic effects of 5-aza and SAHA can be rescued by depletion of PRRs such as cGAS and MAVS, and potentiated by depletion of the RNA-editing enzyme ADAR1. Together, our results demonstrate preclinical activity of combined DNMT and HDAC inhibition against chondrosarcomas and suggest that targeted epigenetic therapies could represent a new therapeutic approach in the treatment of chondrosarcomas, and this is being tested in an ongoing clinical trial (NCT04340843).

Activation of efficient DNA repair mechanisms after photon and proton irradiation of human chondrosarcoma cells

Although particle therapy with protons has proven to be beneficial in the treatment of chondrosarcoma compared to photon-based (X-ray) radiation therapy, the cellular and molecular mechanisms have not yet been sufficiently investigated. Cell viability and colony forming ability were analyzed after X-ray and proton irradiation (IR). Cell cycle was analyzed using flow cytometry and corresponding regulator genes and key players of the DNA repair mechanisms were measured using next generation sequencing, protein expression and immunofluorescence staining. Changes in metabolic phenotypes were determined with nuclear magnetic resonance spectroscopy. Both X-ray and proton IR resulted in reduced cell survival and a G2/M phase arrest of the cell cycle. Especially 1 h after IR, a significant dose-dependent increase of phosphorylated γH2AX foci was observed. This was accompanied with a reprogramming in cellular metabolism. Interestingly, within 24 h the majority of clearly visible DNA damages were repaired and the metabolic phenotype restored. Involved DNA repair mechanisms are, besides the homology directed repair (HDR) and the non-homologous end-joining (NHEJ), especially the mismatch mediated repair (MMR) pathway with the key players EXO1, MSH3, and PCNA. Chondrosarcoma cells regenerates the majority of DNA damages within 24 h. These molecular mechanisms represent an important basis for an improved therapy.

Nerve growth factor promotes lysyl oxidase-dependent chondrosarcoma cell metastasis by suppressing miR-149-5p synthesis

Chondrosarcoma is a malignancy of soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is critical for neuronal cell growth, apoptosis, and differentiation, and also appears to promote the progression and metastasis of several different types of tumors, although the effects of NGF upon chondrosarcoma mechanisms are not very clear. We report that NGF facilitates lysyl oxidase (LOX)-dependent cellular migration and invasion in human chondrosarcoma cells, and that NGF overexpression enhances lung metastasis in a mouse model of chondrosarcoma. NGF-induced stimulation of LOX production and cell motility occurs through the inhibition of miR-149-5p expression, which was reversed by PI3K, Akt, and mTOR inhibitors and their respective short interfering RNAs. Notably, levels of NGF and LOX expression correlated with tumor stage in human chondrosarcoma samples. Thus, NGF appears to be a worthwhile therapeutic target for metastatic chondrosarcoma.

Distinctive Evasion Mechanisms to Allow Persistence of Borrelia burgdorferi in Different Human Cell Lines.

Lyme borreliosis is a multisystemic disease caused by the pleomorphic bacteria of the Borrelia burgdorferi sensu lato complex. The exact mechanisms for the infection to progress into a prolonged sequelae of the disease are currently unknown, although immune evasion and persistence of the bacteria in the host are thought to be major contributors. The current study investigated B. burgdorferi infection processes in two human cell lines, both non-immune and non-phagocytic, to further understand the mechanisms of infection of this bacterium. By utilizing light, confocal, helium ion, and transmission electron microscopy, borrelial infection of chondrosarcoma (SW1353) and dermal fibroblast (BJ) cells were examined from an early 30-min time point to a late 9-days post-infection. Host cell invasion, viability of both the host and B. burgdorferi, as well as, co-localization with lysosomes and the presence of different borrelial pleomorphic forms were analyzed. The results demonstrated differences of infection between the cell lines starting from early entry as B. burgdorferi invaded BJ cells in coiled forms with less pronounced host cell extensions, whereas in SW1353 cells, micropodial interactions with spirochetes were always seen. Moreover, infection of BJ cells increased in a dose dependent manner throughout the examined 9 days, while the percentage of infection, although dose dependent, decreased in SW1353 cells after reaching a peak at 48 h. Furthermore, blebs, round body and damaged B. burgdorferi forms, were mostly observed from the infected SW1353 cells, while spirochetes dominated in BJ cells. Both infected host cell lines grew and remained viable after 9 day post-infection. Although damaged forms were noticed in both cell lines, co-localization with lysosomes was low in both cell lines, especially in BJ cells. The invasion of non-phagocytic cells and the lack of cytopathic effects onto the host cells by B. burgdorferi indicated one mechanism of immune evasion for the bacteria. The differences in attachment, pleomorphic form expressions, and the lack of lysosomal involvement between the infected host cells likely explain the ability of a bacterium to adapt to different environments, as well as, a strategy for persistence inside a host.

Complex anterior chest wall reconstruction after extensive oncologic resections: a narrative review.

Objective:This report serves to showcase four cases of rare, malignant primary neoplasms of the anterior chest wall [chondrosarcoma and basal cell carcinoma (BCC)] that thoracic surgeons may encounter, and different approaches to complex reconstruction that may be necessary following resection.Background:Approximately 60% of the anterior chest wall neoplasms are malignant. The most common types of primary sternal tumors are chondrosarcoma and osteosarcoma. While guidelines for resection of these tumors have been previously described in the literature, guidelines regarding reconstructive techniques of the subsequent large defects are infrequently demonstrated.Methods:The medical records of four adult patients with primary chest wall tumors who underwent resection of the sternum from October 2016 to March 2021 were retrospectively reviewed. Radical resection with tumor-free surgical margins offers the best chance for survival, but results in a wide full-thickness defect. Hence, closure of the anterior chest wall defect with skeletal reconstruction is an essential step of the procedure and allows us to highlight surgical techniques and materials that have been used over recent years. Methods described herein include skeletal reconstruction with various hardware or allograft, as well as defect coverage using regional flaps, free tissue transfer, and mesh.Conclusions:Primary chest wall tumors of the sternum are an extremely rare diagnosis with a high malignancy rate. Full-thickness radical en-bloc resection is the most effective treatment option. Subsequent reconstruction of a wide chest wall defect is the most challenging aspect, though crucial in the preservation of the rigidity of the chest wall and protection of underlying structures. Different techniques and materials have been described without clear guidelines in treatment approaches; this paper serves to delineate and describe techniques that achieved successful outcomes.

WISP-3 Stimulates VEGF-C-Dependent Lymphangiogenesis in Human Chondrosarcoma Cells by Inhibiting miR-196a-3p Synthesis.

Chondrosarcoma is a malignant bone tumor with high metastatic potential. Lymphangiogenesis is a critical biological step in cancer metastasis. WNT1-inducible signaling pathway protein 3 (WISP-3) regulates angiogenesis and facilitates chondrosarcoma metastasis, but the role of WISP-3 in chondrosarcoma lymphangiogenesis is unclear. In this study, incubation of chondrosarcoma cells with WISP-3 increased the production of VEGF-C, an important lymphangiogenic factor. Conditioned medium from WISP-3-treated chondrosarcoma cells significantly enhanced lymphatic endothelial cell tube formation. WISP-3-induced stimulation of VEGF-C-dependent lymphangiogenesis inhibited miR-196a-3p synthesis in the ERK, JNK, and p38 signaling pathways. This evidence suggests that the WISP-3/VEGF-C axis is worth targeting in the treatment of lymphangiogenesis in human chondrosarcoma.

Co-Treatment with the Epigenetic Drug, 3-Deazaneplanocin A (DZNep) and Cisplatin after DZNep Priming Enhances the Response to Platinum-Based Therapy in Chondrosarcomas.

Simple SummaryChondrosarcoma is a rare bone tumor characterized by the secretion of a cartilage-like extracellular matrix. Its treatment poses major challenges, since chondrosarcoma is resistant to chemotherapy and radiotherapy. Consequently, chondrosarcoma treatment has been limited over the past 30 years, and consists in the surgical resection of the tumor. Increasing evidence suggests that future cancer therapies will be enhanced by the combination of epigenetic and conventional antitumor agents, leading to further investigations to combine 3-Deazaneplanocin A (DZNep), an epigenetic drug, with existing antitumoral agents. We show by in vitro and in vivo experiments that an optimised DZNep/cisplatin combination reduces chondrosarcoma viability and induces apoptosis more effectively than each of the drugs alone. These results demonstrate the potential use of this epigenetic-chemotherapeutic combination approach for further studies and management of chondrosarcoma treatment.Background: We have previously shown that 3-Deazaneplanocin A (DZNep) induces apoptosis in chondrosarcomas. Herein, we tested whether the combination of this epigenetic drug to a standard anticancer therapy may enhance the response to each drug in these bone tumors. Methods: Two chondrosarcoma cell lines (SW1353 and JJ012) were cultured in the presence of DZNep and/or cisplatin. Cell growth was evaluated by counting viable cells, and apoptosis was determined by Apo2.7 expression by flow cytometry. In vivo, the antitumoral effect of the DZNep/cisplatin combination was assessed through measurements of tumor volume of JJ012 xenografts in nude mice. Results: In vitro, the DZNep/cisplatin combination reduced cell survival and increased apoptosis compared to each drug alone in chondrosarcomas, but not in normal cells (chondrocytes). This enhancement of the antitumoral effect of the DZNep/cisplatin combination required a priming incubation with DZNep before the co-treatment with DZNep/cisplatin. Furthermore, in the chondrosarcoma xenograft mice model, the combination of both drugs more strongly reduced tumor growth and induced more apoptosis in tumoral cells than each of the drugs alone. Conclusion: Our results show that DZNep exposure can presensitize chondrosarcoma cells to a standard anticancer drug, emphasizing the promising clinical utilities of epigenetic-chemotherapeutic drug combinations in the future treatment of chondrosarcomas.

Update and interpretation of 2021 National Comprehensive Cancer Network (NCCN) "Clinical Practice Guidelines for Bone Tumors"

The incidence of primary malignant bone tumors is low, and clinical cognition is insufficient. The establishment of diagnostic criteria is of great significance for prognosis of tumors. National Comprehensive Cancer Network (NCCN) regularly publishes "Clinical Practice Guidelines for Bone Tumors" to summarize the latest treatment progress of bone tumors. In the latest version of the guidelines released in November 2020, surgery is the main treatment for chondrosarcoma, chordoma, and giant cell tumor of bone, which can be combined with radiotherapy or targeted therapy. Ewing's sarcoma and osteosarcoma are treated by surgery combined with chemotherapy. Immunotherapy can be used to treat high-grade undifferentiated pleomorphic sarcoma. For recurrent tumors, surgery combined with radiotherapy, chemotherapy, and/or targeted therapy can be used for control. The guidelines provide a reference for the standard treatment of bone tumors.

Visfatin Promotes the Metastatic Potential of Chondrosarcoma Cells by Stimulating AP-1-Dependent MMP-2 Production in the MAPK Pathway.

Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma.

Sulforaphane-loaded hyaluronic acid-poloxamer hybrid hydrogel enhances cartilage protection in osteoarthritis models

Sulforaphane (SFN) is an isothiocyanate with anti-arthritic and immuno-regulatory activities, supported by the downregulation of NF-κB pathway, reduction on metalloproteinases expression and prevention of cytokine-induced cartilage degeneration implicated in OA progression. SFN promising pharmacological effects associated to its possible use, by intra-articular route and directly in contact to the site of action, highlight SFN as promising candidate for the development of drug-delivery systems. The association of poloxamers (PL) and hyaluronic acid (HA) supports the development of osteotrophic and chondroprotective pharmaceutical formulations. This study aims to develop PL-HA hybrid hydrogels as delivery systems for SFN intra-articular release and evaluate their biocompatibility and efficacy for osteoarthritis treatment. All formulations showed viscoelastic behavior and cubic phase organization. SFN incorporation and drug loading showed a concentration-dependent behavior following HA addition. Drug release profiles were influenced by both diffusion and relaxation of polymeric chains mechanisms. The PL407-PL338-HA-SFN hydrogel did not evoke pronounced cytotoxic effects on either osteoblast or chondrosarcoma cell lines. In vitro/ex vivo pharmacological evaluation interfered with an elevated activation of NF-κB and COX-2, increased the type II collagen expression, and inhibited proteoglycan depletion. These results highlight the biocompatibility and the pharmacological efficacy of PL-HA hybrid hydrogels as delivery systems for SFN intra-articular release for OA treatment.

SUMOylation Is Associated with Aggressive Behavior in Chondrosarcoma of Bone.

Simple SummarySUMO is a ubiquitin-like post-translational modification important for many cellular processes and is suggested to play a role in cancer cell cycle progression. The aim of our study is to understand the role of SUMOylation in tumor progression and aggressiveness. Chondrosarcoma of bone was employed as a model to investigate if SUMOylation contributes to its aggressiveness. We confirmed that SUMO expression levels correlate with aggressiveness of chondrosarcoma and disease outcome. Inhibition of SUMOylation showed promising effects on reduction of chondrosarcoma growth in vitro. Our study implies that SUMO expression could be used as a potential biomarker for disease outcome in chondrosarcoma.Multiple components of the SUMOylation machinery are deregulated in various cancers and could represent potential therapeutic targets. Understanding the role of SUMOylation in tumor progression and aggressiveness would increase our insight in the role of SUMO in cancer and clarify its potential as a therapeutic target. Here we investigate SUMO in relation to conventional chondrosarcomas, which are malignant cartilage forming tumors of the bone. Aggressiveness of chondrosarcoma increases with increasing histological grade, and a multistep progression model is assumed. High-grade chondrosarcomas have acquired an increased number of genetic alterations. Using immunohistochemistry on tissue microarrays (TMA) containing 137 chondrosarcomas, we showed that higher expression of SUMO1 and SUMO2/3 correlates with increased histological grade. In addition, high SUMO2/3 expression was associated with decreased overall survival chances (p = 0. 0312) in chondrosarcoma patients as determined by log-rank analysis and Cox regression. Various chondrosarcoma cell lines (n = 7), especially those derived from dedifferentiated chondrosarcoma, were sensitive to SUMO inhibition in vitro. Mechanistically, we found that SUMO E1 inhibition interferes with cell division and as a consequence DNA bridges are frequently formed between daughter cells. In conclusion, SUMO expression could potentially serve as a prognostic biomarker.

A Proteomic Study Suggests Stress Granules as New Potential Actors in Radiation-Induced Bystander Effects.

Besides the direct effects of radiations, indirect effects are observed within the surrounding non-irradiated area; irradiated cells relay stress signals in this close proximity, inducing the so-called radiation-induced bystander effect. These signals received by neighboring unirradiated cells induce specific responses similar with those of direct irradiated cells. To understand the cellular response of bystander cells, we performed a 2D gel-based proteomic study of the chondrocytes receiving the conditioned medium of low-dose irradiated chondrosarcoma cells. The conditioned medium was directly analyzed by mass spectrometry in order to identify candidate bystander factors involved in the signal transmission. The proteomic analysis of the bystander chondrocytes highlighted 20 proteins spots that were significantly modified at low dose, implicating several cellular mechanisms, such as oxidative stress responses, cellular motility, and exosomes pathways. In addition, the secretomic analysis revealed that the abundance of 40 proteins in the conditioned medium of 0.1 Gy irradiated chondrosarcoma cells was significantly modified, as compared with the conditioned medium of non-irradiated cells. A large cluster of proteins involved in stress granules and several proteins involved in the cellular response to DNA damage stimuli were increased in the 0.1 Gy condition. Several of these candidates and cellular mechanisms were confirmed by functional analysis, such as 8-oxodG quantification, western blot, and wound-healing migration tests. Taken together, these results shed new lights on the complexity of the radiation-induced bystander effects and the large variety of the cellular and molecular mechanisms involved, including the identification of a new potential actor, namely the stress granules.

Ca2+ -activated K+ channel KCa 1.1 as a therapeutic target to overcome chemoresistance in three-dimensional sarcoma spheroid models.

The large‐conductance Ca2+‐activated K+ channel KCa1.1 plays a pivotal role in tumor development and progression in several solid cancers. The three‐dimensional (3D) in vitro cell culture system is a powerful tool for cancer spheroid formation, and mimics in vivo solid tumor resistance to chemotherapy in the tumor microenvironment (TME). KCa1.1 is functionally expressed in osteosarcoma and chondrosarcoma cell lines. KCa1.1 activator‐induced hyperpolarizing responses were significantly larger in human osteosarcoma MG‐63 cells isolated from 3D spheroid models compared with in those from adherent 2D monolayer cells. The present study investigated the mechanisms underlying the upregulation of KCa1.1 and its role in chemoresistance using a 3D spheroid model. KCa1.1 protein expression levels were significantly elevated in the lipid‐raft‐enriched compartments of MG‐63 spheroids without changes in its transcriptional level. 3D spheroid formation downregulated the expression of the ubiquitin E3 ligase FBXW7, which is an essential contributor to KCa1.1 protein degradation in breast cancer. The siRNA‐mediated inhibition of FBXW7 in MG‐63 cells from 2D monolayers upregulated KCa1.1 protein expression. Furthermore, a treatment with a potent and selective KCa1.1 inhibitor overcame the chemoresistance of the MG‐63 and human chondrosarcoma SW‐1353 spheroid models to paclitaxel, doxorubicin, and cisplatin. Among several multidrug resistance ATP‐binding cassette transporters, the expression of the multidrug resistance‐associated protein MRP1 was upregulated in both spheroids and restored by the inhibition of KCa1.1. Therefore, the pharmacological inhibition of KCa1.1 may be an attractive new strategy for acquiring resistance to chemotherapeutic drugs in the TME of KCa1.1‐positive sarcomas.

Retraction Note to: XBP1S protects cells from ER stress-induced apoptosis through Erk1/2 signaling pathway involving CHOP.

The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER), and the transcription factor X-box binding protein 1 spliced (XBP1S), a regulator of the UPR, is known to be important for ER stress (ERS)-mediated apoptosis and cell growth, but the molecular mechanism underlying these processes remains unexplored. Here, we report that knockdown of XBP1S by an siRNA silencing approach increased the expression of ERS-associated molecules. The overexpression of XBP1S stimulated, whereas its knockdown inhibited, cell proliferation in chondrocytes and chondrosarcoma cells; in addition, overexpression of XBP1S inhibited, while its repression enhanced, ERS-mediated apoptosis in chondrocytes and chondrosarcoma cells. Furthermore, XBP1S-mediated inhibition of apoptosis in response to ERS is through the Erk1/2 signaling pathway and down-regulation CHOP transcription factor. CHOP is one of the key downstream molecules known to be involved in ERS-mediated apoptosis. Collectively, these findings reveal a novel critical role of XBP1S in ERS-mediated apoptosis and the molecular mechanisms involved.

Abstract 1350: Regulation of pH by growth factors is dependent on the expression of the calcineurin homologous protein-2 in human bone sarcoma cells

Abstract Bone sarcoma is a malignant tumor that includes multiple subtypes. The osteosarcoma is the sixth most common malignancy in adolescents, while chondrosarcoma is primarily a disease of adults. Current treatments for both osteosarcoma and chondrosarcoma have not demonstrated improvement in patients' survival over the past three decades. Extracellular acidosis affects osteoblast and chondrocyte function by reducing bone mineralization and increasing production of cartilage matrix, respectively. Thereby, it weakens bone matrix and expands cartilage matrix, and may play a role in the development of bone characteristics seen in patients with osteosarcoma or chondrosarcoma. Development of extracellular acidosis in cancer is due to dysregulation of pH dynamics mediated by constitutive activation of Na+/H+ exchanger-1 (NHE1) activity, the main transporter responsible for pH regulation. Current therapeutic agents that target inhibition of NHE1 activity are ineffective due to broad inhibitory effects. The calcineurin homologous protein (CHP) family binds to and regulates NHE1 activity. CHP isoform 1 (CHP1) is expressed in non-cancerous cells and forms a dynamic complex with NHE1. On the other hand, CHP isoform 2 (CHP2) is expressed primarily in cancerous cells and has a stronger binding affinity to NHE1 compared with CHP1. We hypothesize that CHP2 binding to NHE1 in cancer cells induces the over-activity of NHE1, making the extracellular pH of cancer cells more acidic than non-cancerous cells. We measured CHP1 or CHP2 protein expression levels in human osteoblast (hFOB), osteosarcoma (143B), and chondrosarcoma (SW1353) cells and studied whether the levels of CHP2 protein expression affected NHE activity in these cell lines. We determined that: 1. hFOB, 143B, and SW1353 cells expressed mainly NHE1; NHE activity measured using spectrofluorometry was completely blocked by a highly selective NHE1 inhibitor (zoniporide, 10-8 M); 2. NHE1 activity was increased by serum-nutrient deprivation, used to mimic a cancerous microenvironment and NHE1 over-activity was associated with increased levels of CHP2 protein expression; 3. silencing of CHP2 by shRNA inhibited NHE1 activity in response to serum-nutrient deprivation in 143B or SW1353 cells and restored the NHE1 response inducted by serum-deprivation in non-cancerous cells. Regulation of NHE1 through CHP2 is proposed as a promising novel target in sarcoma treatment and to overcome the wide range of side effects induced by inhibitors of NHE1 activity. Citation Format: Tiffany Chang, Serena S. Luong, Adam P. Zobel, Elitsa Ananieva, Victor Babich, Francesca Di Sole. Regulation of pH by growth factors is dependent on the expression of the calcineurin homologous protein-2 in human bone sarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1350.

Retracted] Antitumor effect of resveratrol on chondrosarcoma cells via phosphoinositide 3‑kinase/AKT and p38 mitogen‑activated protein kinase pathways.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the cell apoptotic data shown in Fig.2 were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 12: 3151-3155, 2015; DOI: 10.3892/mmr.2015.3683].

Retracted] MicroRNA‑10b suppresses the migration and invasion of chondrosarcoma cells by targeting brain‑derived neurotrophic factor.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell Transwell assay data in the article (featured in Figs. 4 and 7) were strikingly similar to data appearing in different form in another article by different authors. Owing to the fact that the contentious data in the above article had already appeared in different form in another article prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 13: 441‑446, 2016; DOI: 10.3892/mmr.2015.4506].

Identification of ZNF704 as a Novel Oncogene and an Independent Prognostic Marker in Chondrosarcoma.

PurposeThe transcription factor zinc finger protein 704 (ZNF704) is implicated in tumorigenesis. However, the underlying role of ZNF704 in the pathogenesis of chondrosarcoma remains not well delineated. This study investigates the expression level, prognostic significance and potential biological function of ZNF704 in human chondrosarcoma.Materials and MethodsThe mRNA and protein levels of ZNF704 in fresh chondrosarcomas and the paired adjacent non-tumor tissues were evaluated using real-time PCR and immunoblotting, respectively. The protein expression of ZNF704 in chondrosarcoma specimens was detected by immunohistochemistry, and the associations among its expression level, clinicopathological characteristics and prognosis were further investigated. Cell viability, colony formation and apoptosis assay were determined in chondrosarcoma cells and a xenograft model with ZNF704 knockdown.ResultsThe expression levels of ZNF704 mRNA and protein in chondrosarcoma tissues were significantly higher than those in the paired adjacent non-tumor tissues and benign cartilage tumors. Clinicopathological analysis revealed that ZNF704 was expressed at higher levels in chondrosarcoma patients with higher histological grade and advanced MSTS stage. We also found that high expression of ZNF704 significantly correlated with a worse overall survival of chondrosarcoma patients. Multivariate Cox regression analysis indicated that ZNF704 was an independent prognostic marker in chondrosarcoma patients. Our in vitro studies demonstrated that knockdown of ZNF704 markedly inhibited chondrosarcoma cell viability, colony formation and induced apoptosis. In a nude mouse xenograft model, ZNF704 knockdown slowed down chondrosarcoma growth by inducing apoptosis in vivo.ConclusionThese findings suggest that ZNF704 may act as a potent oncogene implicated in chondrosarcoma development, and serve as a independent prognostic marker, highlight the potential of ZNF704 as a novel biomarker and therapeutic target for chondrosarcoma.

Dysregulation of Zinc Finger Protein 395 Contributes to the Pathogenesis of Chondrosarcoma.

IntroductionThe transcription factor zinc finger protein 395 (ZNF395) is involved in several cellular responses and tumorigenesis. However, the potential role and clinical significance of ZNF395 in chondrosarcoma are not well investigated. This study determines the expression profile, prognostic value and biological function of ZNF395 in human chondrosarcoma.MethodsThe mRNA and protein expressions of ZNF395 in fresh chondrosarcomas and the matched adjacent non-tumor tissues were assessed using real-time PCR and immunoblotting, respectively. The protein expression of ZNF395 in chondrosarcoma specimens was evaluated by immunohistochemistry, and the relationships among its protein level, clinicopathological parameters and prognosis were further detected. Cell viability, colony formation, migration, invasion and apoptosis assay were evaluated in chondrosarcoma cells with depletion of ZNF395.ResultsThe mRNA and protein expressions of ZNF395 in chondrosarcoma tissues were significantly higher than those in the matched adjacent non-tumor tissues and benign cartilage tumors. Clinical analysis displayed that ZNF395 was expressed at higher levels in chondrosarcoma patients with higher histological grade and advanced MSTS stage. Furthermore, we demonstrated that high expression of ZNF395 correlated with a worse overall survival of chondrosarcoma patients. Multivariate Cox regression analysis indicated that ZNF395 was an independent prognostic marker in chondrosarcoma patients. Functional studies revealed that depletion of ZNF395 markedly inhibited cell viability, colony formation, migration and invasion, and promoted apoptosis in chondrosarcoma.ConclusionThese findings suggest that dysregulation of ZNF395 contributes to chondrosarcoma development, and ZNF395 may act as a potent oncogene and serve as a independently prognostic factor, highlight the potential of ZNF395 as a novel biomarker and therapeutic target for chondrosarcoma.

Tumor Suppressive Role of miR-342-5p in Human Chondrosarcoma Cells and 3D Organoids.

Chondrosarcomas are malignant bone tumors. Their abundant cartilage-like extracellular matrix and their hypoxic microenvironment contribute to their resistance to chemotherapy and radiotherapy, and no effective therapy is currently available. MicroRNAs (miRNAs) may be an interesting alternative in the development of therapeutic options. Here, for the first time in chondrosarcoma cells, we carried out high-throughput functional screening using impedancemetry, and identified five miRNAs with potential antiproliferative or chemosensitive effects on SW1353 chondrosarcoma cells. The cytotoxic effects of miR-342-5p and miR-491-5p were confirmed on three chondrosarcoma cell lines, using functional validation under normoxia and hypoxia. Both miRNAs induced apoptosis and miR-342-5p also induced autophagy. Western blots and luciferase reporter assays identified for the first time Bcl-2 as a direct target of miR-342-5p, and also Bcl-xL as a direct target of both miR-342-5p and miR-491-5p in chondrosarcoma cells. MiR-491-5p also inhibited EGFR expression. Finally, only miR-342-5p induced cell death on a relevant 3D chondrosarcoma organoid model under hypoxia that mimics the in vivo microenvironment. Altogether, our results revealed the tumor suppressive activity of miR-342-5p, and to a lesser extent of miR-491-5p, on chondrosarcoma lines. Through this study, we also confirmed the potential of Bcl-2 family members as therapeutic targets in chondrosarcomas.