Guangxin Zhou

MicroRNAs in osteosarcoma: From biological players to clinical contributors, a review

Osteosarcoma is a primary malignant bone tumour with high morbidity that occurs mainly in children and adolescents. While the molecular basis of osteosarcoma has received considerable attention, the cellular and molecular mechanisms underlying pre- and postoperative metastasis formation and the development of chemoresistance remain unclear. MicroRNAs (miRNAs), a class of 22-nucleotide noncoding RNAs, have emerged as critical components of gene-regulatory networks controlling numerous important pathophysiological processes, including the initiation and progression of cancers. Studies on miRNAs have opened new avenues for both the diagnosis and treatment of cancer. This review discusses the roles of miRNAs in osteosarcoma and their potential applications for the diagnosis, prognosis and treatment of this malignancy. As a rapidly evolving field of basic and biomedical science, miRNA research will have a revolutionary impact on the management of osteosarcoma.

Vasculogenic mimicry: a new prognostic sign of human osteosarcoma.

Vasculogenic mimicry (VM), a formation of nonendothelial microvascular channels, has been generally recognized as a new pattern of neovascularization in aggressive malignancies. However, whether VM is present and clinically significant in osteosarcoma remains unknown. We identified VM by CD34/periodic acid-Schiff double staining of osteosarcoma specimens before chemotherapy and investigated its prognostic implications. Tumors were also immunohistochemically stained for focal adhesion kinase (FAK) and migration inducing gene 7 (Mig-7) to determine whether these markers are associated with the occurrence of VM. VM was found in 15 of 66 osteoblastic-type osteosarcoma samples (22.7%), and the incidence of VM did not differ with respect to patient sex, age, tumor size, tumor site, surgical type, or histologic response to preoperative chemotherapy. However, Kaplan-Meier survival analysis determined that the presence of VM and the tumor necrosis rate after preoperative chemotherapy are associated with both the overall survival (P = .011 and P = .040, respectively) and metastasis-free survival (P = .002 and P = .045, respectively). Furthermore, Cox proportional hazards analysis showed that the presence of VM and the histologic response to preoperative chemotherapy were independent indicators for both poor overall survival (P = .007 and P = .024, respectively) and poor metastasis-free survival (P = .002 and P = .027, respectively). The expression level of FAK and Mig-7 were higher in the VM group than the non-VM group (P = .017 and P = .021, respectively). These results demonstrate the presence of VM in osteoblastic osteosarcoma and suggest that VM is an unfavorable prognostic factor with FAK and Mig-7 expressions as a potential mechanism of VM formation in osteosarcoma.

Identification of miR-199a-5p in serum as noninvasive biomarkers for detecting and monitoring osteosarcoma

Emerging evidence has suggested that circulating microRNAs (miRNAs) in serum/plasma can serve as noninvasive biomarkers for cancer detection; however, little is known about circulating miRNA profiles in osteosarcoma, a primary malignant bone tumor with high morbidity in young adults and adolescents. The objective of this study was to investigate whether circulating miRNAs in serum could be a useful biomarker for detecting osteosarcoma and monitoring tumor dynamics. Serum samples were obtained from 60 patients before surgery, 28 patients after 1 month of surgery, and 60 healthy individuals. The study was divided into three steps: (1) initial screening of the profiles of circulating miRNAs in pooled serum samples from both healthy controls and pre- and postoperative osteosarcoma patients using a TaqMan low-density qPCR array (TLDA); (2) evaluation of miRNA concentration in individual serum samples from 60 preoperative osteosarcoma patients and 60 healthy controls by a quantitative RT-PCR assay; and (3) evaluation of miRNA concentration in paired serum samples from 28 pre- and postoperative osteosarcoma patients by a quantitative RT-PCR assay. The initial analysis showed that concentrations of serum miRNAs were significantly altered between preoperative osteosarcoma patients and healthy controls and between pre- and postoperative osteosarcoma patients. The quantitative RT-PCR assay showed that serum miR-199a-5p concentrations were significantly higher in osteosarcoma patients than in controls. The value of the area under the ROC curve was 0.8606. Serum levels of miR-199a-5p were significantly lower in post- than preoperative samples. The results indicated the potential of circulating miRNAs as novel noninvasive biomarkers for detecting and monitoring osteosarcoma.

Autophagy mediated CoCrMo particle-induced peri-implant osteolysis by promoting osteoblast apoptosis

Wear particle-induced osteolysis is the leading cause of aseptic loosening, which is the most common reason for THA (total hip arthroplasty) failure and revision surgery. Although existing studies suggest that osteoblast apoptosis induced by wear debris is involved in aseptic loosening, the underlying mechanism linking wear particles to osteoblast apoptosis remains almost totally unknown. In the present study, we investigated the effect of autophagy on osteoblast apoptosis induced by CoCrMo metal particles (CoPs) in vitro and in a calvarial resorption animal model. Our study demonstrated that CoPs stimulated autophagy in osteoblasts and PIO (particle-induced osteolysis) animal models. Both autophagy inhibitor 3-MA (3-methyladenine) and siRNA of Atg5 could dramatically reduce CoPs-induced apoptosis in osteoblasts. Further, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Moreover, 3-MA also prevented osteoblast apoptosis in an antiautophagic way when tested in PIO model. Collectively, these results suggest that autophagy plays a key role in CoPs-induced osteolysis and that targeting autophagy-related pathways may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.

MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma.

Osteosarcoma (OS) is the most common primary bone malignancy and remains a leading cause of cancer-related deaths in adolescents. Emerging evidence indicates that microRNAs (miRNAs) are correlated with clinical and biological characteristics of OS. However, the involvement of miR-199a-5p in OS development remains unclear. In this study, we examined the function of miR-199a-5p in vitro and in vivo. The results showed that miR-199a-5p was significantly up-regulated in OS patient tissues and cells. The inhibition of miR-199a-5p led to a significant decrease in cell proliferation and tumour growth. We further demonstrated that miR-199a-5p could directly bind to the 3′UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27, thereby stimulating STAT3 activation and cell cycle progression in OS cells. Rescue experiments of PIAS3 and p27 further revealed that PIAS3 and p27 were functional targets of miR-199a-5p. Moreover, enhancing the expressions of both PIAS3 and p27 using miR-199a-5p-targeted inhibitors in an OS xenograft model was shown to be a promising approach for OS clinical therapy. Our findings indicate that the pathway of miR-199a-5p targeting both PIAS3 and p27 is a possible mechanism that contributes to tumour growth in OS.

Composite Reconstruction of the Hip Following Resection of Periacetabular Tumors : Middle-Term Outcome

The records of 18 patients with periacetabular tumors who underwent composite reconstruction of the hip following resection of periacetabular tumors were analyzed retrospectively. The mean follow-up period was 49.4 months (range, 28-100 months). During follow-up, 3 patients died and one had recurrence. Fifteen patients achieved favorable walking function; 8 had normal hip function and 7 had partial recovery of flexion function of the hip. The mean MSTS rating for hip function was 76.9%. Two patients had common peroneal nerve injury which was resolved in one of them. Middle-term follow-up showed that composite reconstruction of the hip following resection of periacetabular tumors can effectively remove tumors and provide favorable hip function for these patients. This approach is simple and less costly, and can be widely used.

Research progress on the livin gene and osteosarcomas.

Osteosarcoma is a common malignant tumor of bone, but mechanisms underlying its development are still unclear. At present, it is believed that the inhibition of normal apoptotic mechanisms is one of the reasons for the development of tumors, so specific stimulation of tumor cell apoptosis can be considered as an important therapeutic method. Livin, as a member of the newly discovered inhibitor of apoptosis proteins (IAPs) family, has specifically high expression in tumor tissues and can inhibit tumor cell apoptosis through multiple ways, which can become a new target for malignant tumor treatment (including osteosarcoma) and might of great significance in the clinical diagnosis of tumors and the screening of anti-tumor agents and carcinoma treatment.

Preparation and Antitumor Activity of a Polymeric Derivative of Methotrexate

Abstract:A polymer-drug conjugate was developed by conjugating amino bonds of methotrexate (MTX) to succinoylated &agr;,&bgr;-poly[(2-hydroxyethyl)-L-aspartamide] (PHEA). The therapeutic efficacy of PHEA-MTX was evaluated in vitro and in vivo. PHEA-MTX showed sustained release properties when incubated in pH 5.5 and pH 7.4 buffering solutions at 37°C. PHEA-MTX induced MG63 cell apoptosis in a time-dependent and concentration-dependent manner in vitro and inhibited the growth of S180 sarcoma in vivo. PHEA-MTX was more potent and, more importantly, displayed less systemic toxicity than free MTX. The enhanced therapeutic effects of PHEA-MTX suggest that the PHEA-MTX conjugate may have a greater potential for chemotherapy of cancers.

Mechanical and Biological Properties of a Biodegradable Mg-Zn-Ca Porous Alloy: Mechanical And Biosecurity Of Porous Mg Alloy

As promising alternative to current metallic biomaterials, the porous Mg scaffold with a 3‐D open‐pore framework has drawn much attention in recent years due to its suitable biodegradation, biocompatibility, and mechanical properties for human bones. This experiments aim is to study the mechanical properties, biosafety, and osteogenesis of porous Mg‐Zn alloy.