Xu Hu

Xinqiao Hospital, Ch’ung-ch’ing-shih, Chongqing Shi, China

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Publications (9)25.89 Total impact

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    ABSTRACT: Osteosarcoma is the most common primary malignant bone tumor and affects a significant portion of pediatric oncology patients. Although surgery and adjuvant chemotherapy confer significant survival benefits, many patients go on to develop metastatic disease, particularly to the lungs, secondary to development of drug resistance. Inhibition of protein phosphatase 2A with the small molecule, LB100, has demonstrated potent chemo- and radio-sensitizing properties in numerous pre-clinical tumor models. In this study, we showed that LB100 overcame DNA repair mechanisms in osteosarcoma cells treated with cisplatin, in vitro, and recapitulated these findings in an in vivo xenograft model. Notably, the addition of LB100 to cisplatin prevented development of pulmonary metastases in the majority of treated animals. Our data indicated the mechanism of chemo-sensitization by LB100 involved abrogation of the ATM/ATR-activated DNA damage response, leading to hyperphosphorylation of Chk proteins and persistent cyclin activity. In addition, LB100 exposure suppressed Akt signaling, leading to Mdm2-mediated proteasomal degradation of functional p53. Taken together, LB100 prevented repair of cisplatin-induced DNA damage, resulting in mitotic catastrophe and cell death.
    Cell cycle (Georgetown, Tex.) 04/2015; DOI:10.1080/15384101.2015.1041693 · 5.01 Impact Factor
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    ABSTRACT: Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 458(2). DOI:10.1016/j.bbrc.2015.01.097 · 2.28 Impact Factor
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    ABSTRACT: Bone loss is one of the major complications of advanced cancers such as breast cancer, prostate cancer, and lung cancer. Extensive research has revealed that the receptor activator of NF-κB ligand (RANKL), which is considered to be a key factor in osteoclast differentiation, plays an important role in cancer-associated bone resorption. Therefore, agents that can suppress this bone loss have therapeutic potential. In this study, we detected whether quetiapine (QUE), a commonly used atypical antipsychotic drug, can inhibit RANKL-induced osteoclast differentiation in vitro and prevent human breast cancer-induced bone loss in vivo. RAW 264.7 cells and bone marrow-derived macrophages (BMMs) were used to detect inhibitory effect of QUE on osteoclastogenesis in vitro. Mouse model of breast cancer metastasis to bone was used to test suppressive effect of QUE on breast cancer-induced bone loss in vivo. Our results show that QUE can inhibit RANKL-induced osteoclast differentiation from RAW 264.7 cells and BMMs without signs of cytotoxicity. Moreover, QUE reduced the occurrence of MDA-MB-231 cell-induced osteolytic bone loss by suppressing the differentiation of osteoclasts. Finally, molecular analysis revealed that it is by inhibiting RANKL-mediated MAPK and NF-κB signaling pathways that QUE suppressed the osteoclast differentiation. We demonstrate, for the first time, the novel suppressive effects of QUE on RANKL-induced osteoclast differentiation in vitro and human breast cancer-induced bone loss in vivo, suggesting that QUE may be a potential therapeutic drug for osteolysis treatment.
    Breast Cancer Research and Treatment 02/2015; 149(3):705-14. DOI:10.1007/s10549-015-3290-x · 4.20 Impact Factor
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    ABSTRACT: Ankylosing spondylitis (AS) is a severe chronic inflammatory disease that may ultimately result in the development of a 'bamboo‑like' spine. Although the pathological changes that occur in AS have been extensively investigated, the mechanism underlying spinal fusion during AS remains elusive. Differentially expressed genes (DEGs) in paraspinal tissues from patients with AS compared with those from healthy controls were therefore investigated. Polymerase chain reaction (PCR)‑based suppression subtractive hybridization was performed using total mRNA from the supraspinal ligaments of three patients with AS and three patients with spinal fractures as controls. From this, 27 genes were identified in all of the three independent forward libraries, which were defined as DEGs associated with AS. Reverse transcription‑quantitative PCR demonstrated that six DEGs were overexpressed in the tissues from patients with AS compared with those from individuals in the control group, including those encoding transforming growth factor β types I and III receptor, vascular endothelial growth factor, matrix metalloproteinase‑3, core‑binding factor α1 and bone morphogenetic protein 2. Western blot analysis showed increased expression in all six of these proteins in the samples from patients with AS compared with those in the control groups. These findings suggested that changes in the expression of these genes and proteins are associated with the development of spinal fusion during the pathogenesis of AS. Furthermore, these genes may be novel markers of the risk of developing AS, in addition to being targets for the treatment of this disease.
    Molecular Medicine Reports 01/2015; DOI:10.3892/mmr.2015.3272 · 1.48 Impact Factor
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    ABSTRACT: Breast cancer bone metastases are attributed to multiple cellular and molecular interactions between the cancer cells and the bone microenvironment. Some breast cancers (about 10%) manifest predominant osteoblastic bone metastases. However, the effects of cancer cell-produced factors on osteoblastic differentiation are not fully understood. Semaphorin 3A (Sema 3A) is a newly identified regulatory factor of bone rebuilding. In the present study, we demonstrated that human breast cancer MCF-7 cells, which preferentially form osteoblastic bone metastases, exhibited increased Sema 3A expression levels. We also found that MCF-7 cell-derived Sema 3A stimulated osteoblastic differentiation and nuclear β-catenin accumulation, and these effects could be blocked by shRNA Sema 3A or a Sema 3A-neutralizing antibody. In conclusion, our data suggest that MCF-7 cell-derived Sema 3A plays a causative role in osteoblastic bone metastases progression by stimulating osteoblastic differentiation.
    International journal of clinical and experimental pathology 01/2015; 8(2):1584-93. · 1.78 Impact Factor
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    ABSTRACT: BACKGROUND Prostate cancer metastasis to bone is the second most commonly diagnosed malignant disease among men worldwide. Such metastatic disease is characterized by the presence of osteoblastic bone lesions, and is associated with high rates of mortality. However, the various mechanisms involved in prostate cancer-induced osteoblastic differentiation have not been fully explored. Semaphorin 3A (Sema 3A) is a newly identified regulator of bone metabolism which stimulates differentiation of pre-osteoblastic cells under physiological conditions. We investigated in this study whether prostate cancer cells can mediate osteoblastic activity through Sema 3A.METHODS We cultured osteoprogenitor MC3T3-E1 cells in prostate cancer-conditioned medium, and analyzed levels of Sema 3A protein in diverse prostate cancer cell lines to identify cell lines in which Sema 3A production showed a positive correlation with osteo-stimulation. C4–2 cells were stably transfected with Sema 3A short hairpin RNA to further determine whether Sema 3A contributes to the ability of C4–2 cells to induce osteoblastic differentiation.RESULTSDown-regulation of Sema 3A expression decreased indicators of C4–2 CM-induced osteoblastic differentiation, including alkaline phosphatase production and mineralization. Additionally, silencing or neutralizing Sema 3A in C4–2 cells resulted in diminished β-catenin expression in osteogenitor MC3T3-E1 cells.CONCLUSIONS Our results suggest that prostate cancer-induced osteoblastic differentiation is at least partially mediated by Sema 3A, and may be regulated by the β-catenin signalling pathway. Sema 3A may represent a novel target for treatment of prostate cancer-induced osteoblastic lesions. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 11/2014; 75(4). DOI:10.1002/pros.22923 · 3.57 Impact Factor
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    ABSTRACT: The objective of this study was to explore the relationship between single-nucleotide polymorphisms (SNPs) of the protein kinase C gamma (PRKCG) gene and osteosarcoma susceptibility in Chinese Han population. A total of 610 cases of osteosarcoma patients and 610 healthy individuals were enrolled in this study. TaqMan method was used to compare genotypes and the allelic distribution frequency of three SNPs (rs454006, rs2242245, and rs8103851) in the PRKGG gene between osteosarcoma patients and healthy individuals. Osteosarcoma patients were grouped according to different clinical parameters (age, gender, pathological types, tumor location, Enneking staging, tumor metastasis and treatment) to compare genotype and allele frequency among different groups as well as to explore the relationship between gene polymorphisms and different clinical parameters. The rs454006 polymorphisms of the PRKCG gene include the CC, CT, and TT genotypes. The differences in genotype frequency and allele frequency between osteosarcoma patients and healthy individuals were significant (both P < 0.001). There was no significant different between osteosarcoma patients and healthy individuals in rs8103851 and rs2242245 polymorphisms of the PRKCG gene (both P > 0.05). The differences of the rs8103851 genotype frequency and allele frequency in patients with metastatic osteosarcoma and patients without metastasis were significant (both P < 0.001). The distribution frequencies of the CG and GG genotypes as well as the G allele in patients with metastatic osteosarcoma were higher than in patients without metastasis. The genotype frequency and allele frequency of rs454006 and rs2242245 did not correlate with clinical parameters. The rs454006 polymorphism of the PRKCG gene correlated to osteosarcoma susceptibility and might increase the risk of osteosarcoma. The rs8103851 correlated to metastatic osteosarcoma and could be risk factors for metastatic osteosarcoma.
    Tumor Biology 09/2014; DOI:10.1007/s13277-014-2591-8 · 2.84 Impact Factor
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    ABSTRACT: Objective To examine the histopathological changes in spinal tissues of ankylosing spondylitis (AS) patients. Methods Tissue samples from 10 AS patients and 10 control subjects were obtained. Hematoxylin and eosin, picrosirius, Masson and van Gieson stainings were utilized to determine the pathological changes in tissues. Ultrastructural alterations were examined by electronic microscopy. Proteoglycan levels were assessed by enzyme-linked immunosorbent assays (ELISA). Matrix metalloproteinase-3 (MMP-3), transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) levels were evaluated by immunohistochemistry. ResultsOur results demonstrate that the density of collagen fibrils was reduced in the supraspinous ligaments of AS tissue and fibrils were loosely and irregularly organized as compared to a regular distribution of collagen fibrils in controls. In ligamentum flava from AS patients, activated fibroblasts with enlarged nuclei were detected, while the number of elastic fibers was greatly decreased. Paraspinal muscle tissues of AS patients exhibited increased collagen fibril accumulation and atrophy. Significantly decreased proteoglycan and elevated MMP-3 levels were found in supraspinous ligament samples from AS patients (P < 0.01). Additionally, the levels of TGF-β1 in ligamentum flava and paraspinal muscle tissues of AS patients were increased (P < 0.01). The expression of TNF-α was also upregulated in the ligamentum flavum (P < 0.01), with no significant difference in the paraspinal muscle between control and AS patients (P > 0.05). Conclusions Our findings reveal histopathological changes that occur in certain spinal tissues of AS patients and suggest that increased levels of MMP-3 and TGF-β1 may contribute to the pathogenesis of AS.
    International Journal of Rheumatic Diseases 03/2014; DOI:10.1111/1756-185X.12305 · 1.77 Impact Factor
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    ABSTRACT: Our objective was to observe the role of vascular endothelial growth factor (VEGF) 121 gene transfer in promoting vascular reconstruction and bone repair in femur head necrosis of rabbits. The femoral head necrosis model was induced by injection with ethanol. The necrotic femoral head was transfected with a human adenoviral vector expressing VEGF (Ad-hVEGF121). Bone formation in the subchondral necrotic region was analyzed using histology, by measuring the bone mineral density value, and by observing bone trabecular morphology using image analysis. Revascularization level, bone formation rate, bone quality and quantity, and mineralization level in the subchondral necrotic region of the gene transfection group were significantly higher than the control groups. The control groups had more subchondral bone resorption compared with the gene transfection group. VEGF might promote bone formation and revascularization in the subchondral necrotic region of the femoral head, indirectly protecting the necrotic bone trabecula from absorption and avoiding a reduction in the mechanical function of the subchondral region.
    The Journal of trauma 02/2011; 70(6):1519-23. DOI:10.1097/TA.0b013e3181f31595 · 2.96 Impact Factor