Tielong Liu

Factors Affecting Prognosis of Patients with Giant Cell Tumors of the Mobile Spine: Retrospective Analysis of 102 Patients in a Single Center

BackgroundGiant cell tumor (GCT) of the mobile spine is a benign tumor, but it can be potentially aggressive. There is not much published information on GCT of the mobile spine as a result of rarity of the disease, and there are controversies over prognostic factors of the condition.MethodsA retrospective analysis of GCT of the mobile spine was performed by survival analysis. Recurrence-free survival (RFS) was defined as the interval between the date of surgery and the date of recurrence. The postoperative RFS rate was estimated by the Kaplan–Meier method. Factors with P values of ≤0.1 were subjected to multivariate analysis for RFS by proportional hazard analysis. P values of ≤0.5 were considered statistically significant.ResultsA total of 102 patients with GCT of the mobile spine were included in the study. The mean follow-up period was 39.9 (median 26.0, range 2–153) months. Thirty-eight patients developed recurrence. The univariate and multivariate analysis suggested that age less than 40 years, total spondylectomy either by en bloc or piecemeal method, and administration of bisphosphonate were independent favorable prognostic factors. Subgroup analysis by excluding patients before the year 2000 further confirmed our findings.ConclusionsThe removal of the entire osseous compartment either by en bloc or piecemeal method in combination with the long-term use of bisphosphonate could significantly reduce the recurrence rate of GCT of the mobile spine. Age less than 40 years is a favorable prognostic factor for GCT in the mobile spine.

MiR-126-5p regulates osteoclast differentiation and bone resorption in giant cell tumor through inhibition of MMP-13

Giant cell tumor (GCT) of bone is an aggressive skeletal tumor characterized by localized bone resorption. Matrix metalloproteinase-13 (MMP-13) is the principal proteinase expressed by the stromal cells of GCT (GCTSCs) and also considered to play a crucial role in formation of the osteolytic lesion in GCT. However, the exact mechanism of the regulation of MMP-13 expression in GCTSCs was unknown. In this study, we identified miR-126-5p was significantly downregulated in GCTSCs and affect osteoclast (OC) differentiation and bone resorption by repressing MMP-13 expression at the post-transcriptional level. Thus, our studies show that miR-126-5p plays an important physiological role in multinucleated giant cell formation and osteolytic lesion in GCT.

MiR-451 inhibits cell growth and invasion by targeting CXCL16 and is associated with prognosis of osteosarcoma patients

Recent studies have shown that microRNA-451 (miR-451) was significantly decreased in osteosarcoma tissues and was identified as a tumor suppressor in other types of human cancers. However, its clinical significance and molecular mechanisms in osteosarcoma are still not well understood. MiR-451 levels are evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in osteosarcoma cell lines and in 68 pairs of osteosarcoma and adjacent noncancerous tissues. Then, the associations of miR-451 expression with clinicopathological features of patients were determined. The effects of miR-451 in osteosarcoma cells were examined by MTT and Matrigel invasion assay. The functional target of miR-451 were determined by bioinformatics analysis and validated by luciferase reporter analyses and Western blot assay. Our results showed that the expression of miR-451 was significantly downregulated in osteosarcoma tissues compared with corresponding noncancerous tissues (P < 0.01). Particularly, statistical analysis of primary human osteosarcoma indicated that decreased expression of miR-451 was correlated with metastasis and recurrence. Moreover, the miR-451 force-expression suppressed cell proliferation and invasion in vitro. Based on bioinformatics analysis, we found that chemokine ligand 16 (CXCL16) was identified as a direct functional target of miR-451. Consistent with the effects of miR-451, silencing CXCL16 could phenocopy the effects of miR-451 on phenotypes of osteosarcoma cells. Furthermore, CXCL16 expression was upregulated in osteosarcoma tissues and inversely associated with miR-451 in human osteosarcoma tissues. Our data reveal a downregulated expression of miR-451 in osteosarcoma tissues, which is inversely associated with CXCL16 levels. These observations demonstrated that miR-451 may play an important role in tumor growth and metastasis in osteosarcoma.

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2.

Background/Aims: There have been many studies on the etiology of osteoarthritis (OA) with regard to the function of inflammatory cytokines, the process of cartilage degradation, the function of miR-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. Methods: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1α, HIF-2α, miR-146a and Bcl-2 and autophagy markers ULK-1, ATG-5 were detected by quantitative PCR (Q-PCR) and western blotting. The autophagy marker LC-3 was detected by immunofluorescence. The reciprocal effects between miR-146a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection. Results: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146a expression via HIF-1α, but not HIF-2α, while miR-146a did not reversely affect HIF-1α. The autophagy induced by hypoxia through HIF-1α, miR-146a and Bcl-2. Simply, hypoxia induced HIF-1α, and HIF-1α increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1α nor miR-146a. The absence of both HIF-1α and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. Conclusion: HIF-1α, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1α and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.

MiR-126-5p regulates osteolysis formation and stromal cell proliferation in giant cell tumor through inhibition of PTHrP

Parathyroid hormone-related protein (PTHrP) has been identified to play a crucial role in osteolysis formation and stromal cell (GCTSC) proliferation in giant cell tumor (GCT). MiR-126-5p is an intronic miRNA identified as tumor suppressor in many tumors, but its role in GCT is poorly understood. We found that miR-126-5p was decreased in GCT and could directly regulate PTHrP expression. Furthermore, miR-126-5p could control osteoclast (OC) differentiation, GCTSC proliferation and osteolysis formation in GCT through negative regulation of PTHrP. Thus, these results suggest that miR-126-5p could directly target PTHrP and have a tumor suppressor function in GCT.

Correlative Study of Nerve Root Palsy and Cervical Posterior Decompression Laminectomy and Internal Fixation

This study investigates the probable causes of nerve root palsy through the retrospective study of pre- and postoperative cervical curvature change for patients with cervical spondylosis and incidences of nerve root palsy. A consecutive series of 91 patients with cervical compressive myelopathy treated by laminectomy and internal fixation were reviewed. Nerve root palsy developed in 21 of 91 patients (23%) (group A). The other 70 patients, 41 men and 29 women, were chosen as controls (group B). A neutral lateral cervical spine radiograph was taken of all patients. The overall curvature of the cervical spine, the cervical curvature index, and the change rate were measured and compared.The pre- and postoperative change rate of cervical curvatures in groups A and B was 19.17+/-7.62 and 18.03+/-7.62, respectively. The difference was not statistically significant (P>.05). The pre- and postoperative cervical curvature index change rate in groups A and B was 17.52+/-3.46 and 12.43+/-4.12, respectively. There were statistically significant differences between the 2 groups (P<. 05). This indicated the cervical alignment of patients in group A was changed greatly by traction during operation.In this study, we found that tethering the nerve root caused C5 palsy, but excessive intraoperative traction and the use of internal fixation may be one of the most important reasons for this. The cervical curvature index change rate reflected both a change in cervical height and a change in the overall cervical curvature. It is more sensitive in reflecting the degree of cervical traction and the change of the cervical alignment.

Surgery and prognostic factors of patients with epidural spinal cord compression caused by hepatocellular carcinoma metastases: retrospective study of 36 patients in a single center.

Study Design. A retrospective study of 36 patients with metastatic hepatocellular carcinoma (HCC) of the mobile spine was performed by survival analysis. Objective. To discuss the factors that may affect outcomes of patients with HCC spinal metastases. Summary of Background Data. HCC is a rare tumor in Western countries. However, HCC is common in Far East (Taiwan, Korea, mainland China), where the hepatitis B virus is epidemic. As the mean survival time of patients with HCC has largely increased in recent years, it is now more common to encounter a patient with epidural spinal cord compression caused by HCC spinal metastases in clinic. Methods. The univariate and multivariate analyses of various clinical factors were performed to identify independent variables that could predict prognosis. The survival rate was estimated by the Kaplan-Meier method, and differences were analyzed by the log-rank test. Factors with P values of 0.1 or less were subjected to multivariate analysis for survival rate by multivariate Cox proportional hazards analysis. Results. A total of 36 patients with metastatic HCC of the mobile spine were included in the study. Age (⩽45 yr/>45 yr), duration of preoperative symptoms (<6 mo/≥6 mo), preoperative Frankel score (A–C/D–E), Tomita score (5–7/8–10), and bisphosphonate treatment were suggested as the potential prognostic factors through univariate analysis. However, as they were submitted to the multivariate Cox regression model, only Tomita score was found as an independent prognostic factor. Conclusion. Tomita score no more than 7 is a favorable prognostic factor for HCC metastases in the mobile spine. Level of Evidence: 4

REGg is critical for skin carcinogenesis by modulating the Wnt/b-catenin pathway

Here we report that mice deficient for the proteasome activator, REGγ, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGγ in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ activates Wnt/β-catenin signalling by degrading GSK-3β in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β-catenin. Conversely, MAPK/p38 inactivation or REGγ deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β-catenin pathway.

Cytotoxic T-Lymphocyte Antigen-4 Genetic Variants and Risk of Ewing's Sarcoma

Despite the knowledge of many genetic alterations present in Ewings sarcoma (ES), the complexity of this disease precludes placing its biology into a simple conceptual framework. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) can decrease T-cell activation and attenuate antitumor responses. Polymorphisms in the CTLA-4 gene have been shown to be associated with different diseases. Here, we investigated the association of four CTLA-4 gene polymorphisms, -1661A/G (rs4553808), -318C/T (rs5742909), +49G/A (rs231775), and CT60A/G (rs3087243), with ES in the Chinese population. A total of 308 ES cases and 362 healthy controls were recruited and CTLA-4 polymorphisms were tested by polymerase chain reaction-restriction fragment length polymorphism. Results showed that frequencies of the CTLA-4 gene +49AA genotype, +49A allele, and GTAG haplotype were significantly increased in ES patients compared to healthy controls (odds ratio [OR]=2.42, 95% confidence interval [CI] 1.43-4.09, p<0.001; OR 1.38, 95% CI 1.11-1.73, p=0.005, and OR=1.46, 95% CI 1.06-2.02, p=0.020, respectively). We further compared CTLA-4 polymorphisms in ES patients based on different clinical parameters and data revealed that ES patients with metastasis had higher numbers of the +49AA genotype than those without metastasis (p=0.004). These results indicated that the CTLA-4 polymorphism could be a risk factor for ES and suggested a potential role of CTLA-4 in the metastasis of this malignancy.

Hypoxia-induced microRNA-146a represses Bcl-2 through Traf6/IRAK1 but not Smad4 to promote chondrocyte autophagy.

Abstract It has been shown that hypoxia stimulation promotes chondrocytes autophagy partly through HIF-1α, miR-146a and Bcl-2 progressively, and this mechanism represented the connection among hypoxia, miR-146a and autophagy, and provides a possible therapeutic strategy for osteoarthritis. However, the interaction between miR-146a and Bcl-2 is still unclear. Here in a hypoxic environment, we quantified the three reported miR-146a targets: two inflammation related targets Traf6, IRAK1; and the only reported target in chondrocytes Smad4. We confirmed the regulative function of miR-146a between hypoxia and these genes, and explored the Bcl-2 expression and autophagy level under extrinsic up-regulation of these three gene separately. All the three genes were down-regulated by hypoxia. Surprisingly, Traf6 and IRAK, but not the unique Smad4 in chondrocytes, were restored by antagomiR-146a. Both Ad-Traf6 and Ad-IRAK1 reinstated hypoxia or miR-146a repressed Bcl-2. However, Ad-Smad4 did not affect Bcl-2 in hypoxia or normoxia. The autophagy level showed a reverse variability compared to Bcl-2. Taken together, our results provided evidence that Smad4, the unique reported target for miR-146a in chondrocytes is unusually not involved in the chondrocytes autophagy, while the Traf6 and IRAK1 are the new targets for miR-146a in chondrocytes during autophagy.