Hua Zhou

Recombinant human PDCD5 sensitizes chondrosarcomas to cisplatin chemotherapy in vitro and in vivo

Clinical management of chondrosarcoma remains a challenging problem, largely due to the toxicity and resistance of this tumor to conventional chemotherapy. Programmed Cell Death 5 (PDCD5) is a protein that accelerates apoptosis in different cell types in response to various stimuli, and has been shown to be down-regulated in many cancer tissues. In this study, mRNA and protein levels of PDCD5 were found to be up-regulated in cisplatin-treated SW1353 chondrosarcoma cells compared with untreated cells. Recombinant human PDCD5 (rhPDCD5) was also shown to sensitize chondrosarcoma cells to cisplatin-based chemotherapy, with inhibition of cell growth and apoptosis detected both in vitro and in vivo. Increased expression of Bax and decreased expression of Bcl-2 were also observed, along with release of cytochrome c from mitochondria into the cytosol. Additionally, cleavage of caspase-9 and caspase-3, as well as the cleavage of poly (ADP-ribose) polymerase (PARP), were detected, suggesting that sensitization of chondrosarcoma cells involves the intrinsic mitochondrial apoptosis pathway. In vivo, the treatment of a xenograft model of chondrosarcoma with rhPDCD5 and cisplatin significantly inhibited tumor cell proliferation and induced apoptosis compared to treatment with cisplatin alone. Overall, these data provide a theoretical basis for the administration of rhPDCD5 and cisplatin for the treatment of patients with chondrosarcoma.

Integrated miRNA-mRNA Analysis Revealing the Potential Roles of miRNAs in Chordomas

Introduction Emerging evidence suggests that microRNAs (miRNAs) are crucially involved in tumorigenesis and that paired expression profiles of miRNAs and mRNAs can be used to identify functional miRNA-target relationships with high precision. However, no studies have applied integrated analysis to miRNA and mRNA profiles in chordomas. The purpose of this study was to provide insights into the pathogenesis of chordomas by using this integrated analysis method. Methods Differentially expressed miRNAs and mRNAs of chordomas (n = 3) and notochord tissues (n = 3) were analyzed by using microarrays with hierarchical clustering analysis. Subsequently, the target genes of the differentially expressed miRNAs were predicted and overlapped with the differentially expressed mRNAs. Then, GO and pathway analyses were performed for the intersecting genes. Results The microarray analysis indicated that 33 miRNAs and 2,791 mRNAs were significantly dysregulated between the two groups. Among the 2,791 mRNAs, 911 overlapped with putative miRNA target genes. A pathway analysis showed that the MAPK pathway was consistently enriched in the chordoma tissue and that miR-149-3p, miR-663a, miR-1908, miR-2861 and miR-3185 likely play important roles in the regulation of MAPK pathways. Furthermore, the Notch signaling pathway and the loss of the calcification or ossification capacity of the notochord may also be involved in chordoma pathogenesis. Conclusion This study provides an integrated dataset of the miRNA and mRNA profiles in chordomas, and the results demonstrate that not only the MAPK pathway and its related miRNAs but also the Notch pathway may be involved in chordoma development. The occurrence of chordoma may be associated with dysfunctional calcification or ossification of the notochord.

Prognostic significance of downregulated expression of programmed cell death 5 in chondrosarcoma.

Programmed Cell Death 5 (PDCD5) is a novel apoptosis‐related gene and deregulation of PDCD5 is involved in tumorigenicity. This study was designed to investigate the expression level of PDCD5 and to clarify its clinical significance in chondrosarcoma.

Increased levels of hypoxia-inducible factor-1α are associated with Bcl-xL expression, tumor apoptosis, and clinical outcome in chondrosarcoma

Hypoxia‐inducible factor (HIF)‐1α is a key nuclear transcription factor that regulates the cellular response to hypoxia, and is important for solid tumor growth and survival. However, the underlying role of HIF‐1α in human chondrosarcoma has not been well characterized. This study aims to investigate the expression patterns of HIF‐1α in chondrosarcoma, and its association with clinicopathologic features, Bcl‐xL expression, apoptosis index (AI), and overall survival of patients with chondrosarcoma. Our results shown that the protein levels of HIF‐1α were increased, and the mRNA and protein levels of Bcl‐xL were also increased in SW1353 cells under hypoxic conditions. In eight patients with chondrosarcoma, increased expression of HIF‐1α and Bcl‐xL was detected in chondrosarcoma tissues compared with the paired adjacent normal tissues. Of 34 archival specimens of chondrosarcomas, 20 (58.8%) showed high HIF‐1α protein expression as compared to benign cartilage tumors. Increased HIF‐1α expression was correlated with a higher pathological grade and MSTS stage of chondrosarcoma. Moreover, HIF‐1α expression was significantly associated with Bcl‐xL expression and AI. More significantly, the survival rate of patients with HIF‐1α high tumors was significantly lower than that of patients with HIF‐1α low tumors. These findings suggest that increased HIF‐1α levels mediated up‐regulation of Bcl‐xL play a prominent role in evasion of apoptosis and tumor progression, and can be predictive for the prognosis in human chondrosarcoma.

Differential proteomic profiling of chordomas and analysis of prognostic factors

The recurrence rate of chordoma is high, and the prognosis is poor.

Elevated Levels of Dickkopf-1 Are Associated with β-Catenin Accumulation and Poor Prognosis in Patients with Chondrosarcoma

Background Dickkopf-1 (DKK1) is an antagonist of Wnt/β-catenin signaling implicated in tumorigenesis. However, the biological role of DKK1 and β-catenin involved in chondrosarcoma has not been sufficiently investigated. This study was designed to investigate the expression profiles of DKK1 and β-catenin, and to clarify their clinical values in chondrosarcoma. Methods The mRNA and protein levels of DKK1 and β-catenin in fresh chondrosarcoma and the corresponding non-tumor tissues were analyzed by Real-time PCR and Western blot, respectively. The protein expression patterns of DKK1 and β-catenin were investigated by immunohistochemistry. The associations among DKK1 level, β-catenin accumulation, clinicopathological factors and the overall survival were separately evaluated. Results Both DKK1 and β-catenin levels were remarkably elevated in chondrosarcoma compared with the corresponding non-tumor tissues. High DKK1 level and positive β-catenin accumulation in chondrosarcoma specimens were 58.7% and 53.9%, respectively. Elevated DKK1 level significantly correlated with positive β-catenin accumulation, and they were remarkably associated with histological grade and Musculoskeletal Tumor Society stage. Furthermore, DKK1 level and β-catenin accumulation had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that DKK1 level was an independent prognostic factor for overall survival. Conclusions Elevated DKK1 levels associated with β-catenin accumulation play a crucial role in chondrosarcoma. DKK1 can serve as a novel predictor of poor prognosis in patients with chondrosarcoma.

17β-Estradiol Attenuates Neural Cell Apoptosis Through Inhibition of JNK Phosphorylation in SCI Rats and Excitotoxicity Induced by Glutamate In Vitro

ABSTRACT We investigated whether 17β-estradiol (E2) treatment could prevent the apoptosis of neural cells after spinal cord injury (SCI) and cultured cortical cells through inhibition of JNK (c-Jun N-terminal kinase) phosphorylation. SCI-induced rats were randomly divided into three groups: control, E2-treated, and sham-treated. Five rats from each group were sacrificed at 2, 4, 6, 12, or 24 h postinjury. Apoptotic neural cells were assessed using the TUNEL method. JNK phosphorylation was detected with immunohistochemistry. Cultured cortical cells were pretreated with E2 and the specific JNK inhibitor SP600125 and then treated with glutamate-induced cytotoxicity in vitro. Neuron viability was determined with an methyl thiazolyl tetrazolium (MTT) assay, morphology of apoptotic cells was observed with 4′,6-diamidino-2-phenylindole (DAPI) staining, and JNK phosphorylation was detected using Western blot analysis. Treatment with E2 reduced neuron apoptosis and inhibited JNK phosphorylation. Moreover, the number of apoptotic cells was correlated with JNK phosphorylation 24 h after the rats suffered the SCI. Pretreatment with E2 significantly maintained neural cell viability, attenuated apoptosis, and inhibited JNK phosphorylation induced by glutamate in vitro. These neuroprotective effects of E2 on neural cells were blocked by the co-administration of SP600125. Our results suggest that neuroprotection from E2 is partially mediated by the inhibition of JNK phosphorylation.

Different Approaches for Treating Multilevel Cervical Spondylotic Myelopathy: A Retrospective Study of 153 Cases from a Single Spinal Center.

Objective The optimal surgical treatment for multilevel cervical spondylotic myelopathy (MCSM) remains controversial. This study compared the outcomes of three surgical approaches for MSCM treatment, focusing on the efficacy and safety of a combined approach. Methods This retrospective study included 153 consecutive MCSM patients (100 men, 53 women; mean age ± standard deviation, 55.7 ± 9.4 years) undergoing operations involving ≥3 intervertebral segments. The patients were divided into three groups according to surgical approach: anterior (n = 19), posterior (n = 76), and combined (n = 58). We assessed demographic variables, perioperative parameters, and clinical outcomes ≥12 months after surgery (20.5 ± 7.6 months), including Japanese Orthopaedic Association (JOA) score, improvement, recovery rate, and complications. Results The anterior group had the most favorable preoperative conditions, including the highest preoperative JOA score (12.95 ± 1.86, p = 0.046). In contrast, the combined group had the highest occupancy ratio (48.0% ± 11.6%, p = 0.002). All groups showed significant neurological improvement at final follow-ups, with JOA recovery rates of 59.7%, 54.6%, and 68.9% in the anterior, posterior, and combined groups, respectively (p = 0.163). After multivariable adjustments, the groups did not have significantly different clinical outcomes (postoperative JOA score, p = 0.424; improvement, p = 0.424; recovery rate, p = 0.080). Further, subgroup analyses of patients with occupancy ratios ≥50% showed similar functional outcomes following the posterior and combined approaches. Overall complication rates did not differ significantly among the three approaches (p = 0.600). Occupancy ratios did not have a significant negative influence on postoperative recovery following the posterior approach. Conclusions If applied appropriately, all three approaches are effective for treating MCSM. All three approaches had equivalent neurological outcomes, even in subgroups with high occupancy ratios. Further investigations of surgical approaches to MCSM are needed, particularly prospective multicenter studies with long-term follow-up.

Reduced expression of von Hippel-Lindau protein correlates with decreased apoptosis and high chondrosarcoma grade.

BACKGROUND Mutations and loss of the von Hippel-Lindau (VHL) tumor suppressor gene are associated with most renal cancers as well as several other types of human tumors, but the potential role of the VHL protein (pVHL) in patients with chondrosarcoma has not been characterized. The purpose of the present study was to investigate the expression profiles of pVHL in chondrosarcoma and its association with clinicopathologic parameters, Bax expression, the apoptosis index, and overall survival of patients with chondrosarcoma. METHODS The messenger RNA (mRNA) and protein levels of VHL in fresh specimens from eight chondrosarcomas were studied with use of real-time polymerase chain reaction and Western blot, respectively. The protein expression of VHL and Bax was investigated by means of immunohistochemical analysis of paraffin-embedded clinical specimens from seventeen benign cartilage tumors and thirty-four chondrosarcomas. The apoptosis index in chondrosarcoma was examined by means of the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay. Curves for overall survival were drawn according to the Kaplan-Meier method, and differences were analyzed with the log-rank test. The association of pVHL expression with the clinicopathologic parameters, Bax expression, apoptosis index, and overall survival for patients with chondrosarcoma was also analyzed. RESULTS Levels of VHL protein (p = 0.005) and mRNA (p = 0.008) were significantly reduced in chondrosarcoma tissues as compared with the paired adjacent normal tissues. Immunohistochemical analysis showed decreased pVHL in a significantly higher proportion of chondrosarcomas (64.7%) than benign cartilage tumors (29.4%). pVHL expression was positively correlated with Bax expression and the apoptosis index in chondrosarcoma. Longitudinal studies of a cohort of patients with chondrosarcomas showed that decreased pVHL expression significantly correlated with increased tumor grade (p = 0.026) but was not independently predictive of overall survival. CONCLUSIONS Reduced pVHL expression was associated with decreased apoptosis and increasing chondrosarcoma grade, but the relationship between these findings and chondrosarcoma pathogenesis requires further study.

Cervical Chordoma in Childhood Without Typical Vertebral Bony Destruction: Case Report and Review of the Literature

Study Design. Case report. Objective. We present a giant cervical chordoma without typical vertebral bony destruction in an 11-year-old girl. Summary of Background Data. Chordomas are rare malignant bone tumors that arise at both the cranial and the caudal ends of the axial skeleton, characteristically destroying the bone. Cervical chordomas comprise only 3% to 7% of all chordomas. To our knowledge, there is no case of cervical chordoma in a child, presenting without vertebral body involvement, in English literature. Methods. Discussion on the patient’s clinical, radiologic history, and histopathologic diagnosis of the resected tumor, with a review of the relevant background literature. Results. We report the first case of cervical chordoma in a child without typical vertebral bony destruction, the diagnosis of which was difficult to confirm before and after operation. Conclusion. Giant notochordal rest and benign notochordal cell tumors (BNCTs) need to be recognized for differential diagnosis of this atypical chordoma. A long-term follow-up might be necessary for the diagnosis of this nontypical patient.