Chao Xia

CEP55 promotes the proliferation and invasion of tumour cells via the AKT signalling pathway in osteosarcoma

The molecular mechanisms underlying the development of osteosarcoma (OS) are not fully understood. In this study, we investigated for the first time the clinical significance and biological activity of centrosomal protein 55 (CEP55) in OS. We found that CEP55 was overexpressed in OS, and the CEP55 expression level in OS was correlated with metastasis and poor prognosis. Through in vitro experiments, we confirmed that CEP55 knockdown significantly induced cell cycle arrest at G1 phase and suppressed OS cell proliferation, migration and invasion. In addition, CEP55 knockdown suppressed OS tumour growth in nude mice. Global gene expression profiling of CEP55-silenced MNNG/HOS cells showed that the AKT pathway might be involved in the regulation of OS cell activity. Two downstream factors of AKT signalling, CCND1 and FN1, were found to have significantly higher expression in tumour tissues, and their mRNA expression levels were strongly correlated with CEP55 expression. To conclude, our data suggest that CEP55 can be used as a prognostic marker for OS, highlighting the significance of CEP55 signalling as a putative therapeutic target.

Genetic polymorphism of Nucks1 is associated with the susceptibility of adolescent idiopathic scoliosis

Study Design. A genetic association study. Objective. The aim of this study was to investigate whether NUCKS1 is a susceptible gene of adolescent idiopathic scoliosis (AIS) in Chinese population and to further narrate its association with the clinical phenotypes. Summary of Background Data. AIS is characterized by late onset of menarche and disturbed growth rhythm. Previous studies showed that NUCKS1 is associated with age at menarche and pubertal height growth. Methods. Single-nucleotide polymorphism rs951366 of NUCKS1 was genotyped in 972 patients and 1454 healthy controls. The differences of genotype and allele distributions between AIS patients and healthy controls were evaluated using the &khgr;2 test. One-way analysis of variance test was used to compare the relationship between different genotypes and clinical features including tissue expression of NUCKS1, age at menarche, and curve magnitude. Results. Patients were found to have a significantly lower frequency of CC than the controls (5.9% vs. 10.6%, P < 0.001). Besides, the frequency of allele C was found to be remarkably lower in the patients than the controls (26.4% vs. 30.9%, P < 0.001), with an odds ratio of 0.80 (95% confidential interval = 0.71–0.91). Patients with genotype CC had a remarkably lower age at menarche than patients with genotype TT (12.1 ± 1.7 vs. 12.8 ± 2.4 years, P = 0.02). Patients with genotype TT had a remarkably lower expression level of NUCKS1 than patients with genotype CC (2.8 ± 1.9 vs. 4.3 ± 2.2, P = 0.03). As for curve magnitude, no significant difference was found among patients with different genotypes. Conclusion. Patients with allele T of rs951366 can be more vulnerable to the incidence of AIS as well as a late onset of menarche. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. Level of Evidence: 4

Genetic Variant of GPR126 Gene is Functionally Associated with Adolescent Idiopathic Scoliosis in Chinese Population.

Study Design. A genetic association study of GPR126 gene with adolescent idiopathic scoliosis (AIS) in the Chinese population. Objective. To investigate whether rs9403380, rs6570507, and rs7774095 of GPR126 gene are susceptible locus of AIS and to further determine the functional variants regulating gene expression in tissues of AIS. Summary of Background Data. Previous studies have identified several new susceptibility locus for AIS in GPR126 gene. No studies have, however, investigated GPR126 expression in tissues of AIS, and the regulatory role of susceptible variants in the gene expression remains obscure. Methods. Rs9403380, rs6570507, and rs7774095 were genotyped in 1956 patients with AIS and 2094 controls. The differences of genotype and allele distributions between patients and controls were calculated using chi-square test. Paravertebral muscles were collected from 67 patients with AIS, 20 patients with congenital scoliosis, and 20 patients with lumbar disc herniation. Vertebral bones were obtained in eight patients with AIS and five patients with lumbar disc herniation. Patients with AIS were classified into three groups according to the genotypes of each single-nucleotide polymorphism, and one-way analysis of variance test was used to compare GPR126 expression among different groups and genotypes. Results. All the three single-nucleotide polymorphisms were found significantly associated with AIS. Allele C of rs9403380, allele G of rs6570507, and allele A of rs7774095 can significantly add to the risk of AIS with an odds ratio of 1.17, 1.16, and 1.15, respectively. Patients with AIS were found to have significantly higher GPR126 expression than controls. Moreover, there was significant difference between the expression of the GPR126 in the concave side and convex side of the patients with AIS. Patients with rs9403380 genotype CC have a significantly increased expression of GPR126 than those with TT. Conclusion. Rs9403380 could be a functional variant regulating the expression of GPR126 in the paraspinal muscles of AIS, which may serve as a potential biomarker for the early diagnosis of AIS. Level of Evidence: N/A

Genetic variant of BNC2 gene is functionally associated with adolescent idiopathic scoliosis in Chinese population

Adolescent idiopathic scoliosis (AIS) is a structural curvature of the spine that was estimated to affect millions of children worldwide. Recent study shows that the functional variant rs10738445 could add to the risk of AIS through the regulation of BNC2 gene. This study aims to investigate whether the rs10738445 of BNC2 gene is a functional susceptible locus for AIS in the Chinese population and to further clarify the association of the BNC2 expression with the curve severity. SNP rs10738445 was genotyped in 1952 patients and 2492 controls, and further replicated in 693 patients and 254 controls. We found that patients have a significantly higher frequency of CC than the controls (21.9 vs. 17.7%, p = 0.004 for stage 1; 12.6 vs. 7.9%, p = 0.03 for stage 2). Allele C can significantly add to the risk of AIS with an OR of 1.14–1.24. AIS patients were found to have significantly higher BNC2 expression than the controls. The BNC2 expression was significantly correlated with the curve severity (r = 0.316, p = 0.02). In conclusion, our study suggests a functional role of BNC2 in the development and progression of the spinal deformity in AIS.

Variants of FasL and ABCC5 are predictive of outcome after chemotherapy-based treatment in osteosarcoma

Objectives Previous pharmacogenetics studies showed that genetic variants could be indicative of the response to chemotherapy. We aimed to investigate whether variants of FasL, MSH2, ABCC5, CASP3 and CYP3A4 are associated with the outcome after chemotherapy-based treatment in osteosarcoma. Methods 132 osteosarcoma patients who had completed the neoadjuvant chemotherapy in our center were included. 5-year progression-free survival (PFS) was assessed from the initial treatment to the earliest sign of disease progression or death from any cause. 5 SNPs were genotyped using TaqMan SNP Genotyping Assay, including rs763110 of FasL, rs4638843 of MSH2, rs939338 of ABCC5, rs2720376 of CASP3 and rs4646437 of CYP3A4. Patients were classified into two groups according to the 5-year PFS (event/no event). The chi-square test was used to analyze difference of genotype frequency. Logistic regression analysis was used to determine the independent predictors of the PFS rate. Results The overall 5-year PFS was 61.4% (81/132). Genotype TT/CT of rs763110 and genotype GG/AG of rs939338 were significantly associated with the event of 5-year PFS (p = 0.028 for rs763110; p = 0.039 for rs939338). Patients with no risk allele showed a 5-year PFS of 73.7% (42/57), which was significantly higher than a PFS of 54.2% (26/48) for patients with one risk allele and 48.1% (13/27) for patients with two different risk alleles (p = 0.03). Logistic regression analysis showed that allele T of FasL rs763110 and allele G of ABCC5 rs939338 were independent risk factors of the 5-year PFS. The ORs were 2.14 (95%CI = 1.13–3.35, p = 0.01) for rs763110 and 1.73 (95%CI = 1.05–2.52, p = 0.03) for rs939338, respectively. Conclusions The association of variants of FASL and ABCC5 with survival outcome after chemotherapy was validated in patients with osteosarcoma. Our findings may provide a new insight into a more personalized treatment for patients with osteosarcoma.

A promoter variant of lncRNA GAS5 is functionally associated with the development of osteosarcoma

Highlights • The genetic variant rs145204276 is associated with the susceptibility of OS.• Patients with genotype del/del of rs145204276 had significantly higher expression of GAS5 in the OS tissues.• SNP rs145204276 could play a functional role in the development and progression of OS by altering the methylation status of GAS5 promoter.

Natural History of Postoperative Adding-On in Adolescent Idiopathic Scoliosis: What Are the Risk Factors for Progressive Adding-On?

Purpose To investigate the natural history of distal adding-on in adolescent idiopathic scoliosis (AIS) and to identify risk factors for its progression. Methods Sixty-one AIS patients with distal adding-on occurrence were included. We further classify distal adding-on into progressive and nonprogressive group according to its natural evolution. The first radiograph indicating initiation of adding-on (primary adding-on) and the last follow-up radiograph were compared in terms of the deviation of the first vertebra below instrumentation from the CSVL and the angulation of the first disc below instrumentation. Compared to primary adding-on, progressive adding-on was defined as a further increase of deviation > 5 mm or a further increase of angulation > 5°. Risk factors associated with the progression of adding-on were analyzed. Results Among 61 patients diagnosed with distal adding-on, 24 (39.3%) were progressive and 37 (60.7%) were nonprogressive. Lower Risser grade, open triradiate cartilage, and lowest instrumented vertebra (LIV) proximal to Substantially Stable Vertebra (SSV) were found to be significantly associated with the progressive adding-on. Besides, the distal adding-on was more likely to progress for patients with higher left shoulders than right ones after surgery. Conclusions The risk factors for the progression of adding-on included skeletal immaturity, LIV proximal to SSV, and higher left shoulders after surgery.