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PubMed | Wenzhou University and The 117th Hospital of PLA
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

This study aimed to identify carcinogenic potential-related molecular mechanisms in cancer stem cells (CSCs) in lung cancer. CD133(+) and CD133(-) subpopulations were sorted from A549 cells using magnetic-activated cell sorting. The abilities to form sphere and clone, proliferate, migrate, and invade were compared between CD133(+) and CD133(-) cells, as well as drug sensitivity. Thereafter, microRNA (miRNA) profiles were performed to identify differentially expressed miRNAs between CD133(+) and CD133(-) subpopulation. Following, bioinformatic methods were used to predict target genes for differentially expressed miRNAs and perform enrichment analysis. Furthermore, the mammalian target of rapamycin (mTOR) signaling pathways and CSC property-associated signaling pathways were explored and visualized in regulatory network among competitive endogenous RNA (ceRNA), miRNA, and target gene. CD133(+) subpopulation showed greater oncogenic potential than CD133(-) subpopulation. In all, 14 differentially expressed miRNAs were obtained and enriched in 119 pathways, including five upregulated (hsa-miR-23b-3p, -23a-3p, -15b-5p, -24-3p, and -4734) and nine downregulated (hsa-miR-1246, -30b-5p, -5096, -6510-5p, has-miR-7110-5p, -7641, -3197, -7108-5p, and -6791-5p). For mTOR signaling pathway, eight differential miRNAs (hsa-miR-23b-3p, -23a-3p, -15b-5p, -24-3p, -4734, -1246, -7641, and -3197) and 39 target genes (e.g., AKT1, AKT2, PIK3CB, PIK3CG, PIK3R1, PIK3CA, and PIK3CD) were involved, as well as some ceRNAs. Besides, for CSC property-related signaling pathways, six miRNAs (hsa-miR-1246, -15b-5p, -30b-5p, -3197, -4734, and -7110-5p) were dramatically enriched in Hedgehog, Notch, and Wnt signaling pathways via regulating 108 target genes (e.g., DVL1, DVL3, WNT3A, and WNT5A). The mTOR and CSC property-associated signaling pathways may be important oncogenic molecular mechanisms in CD133(+) A549 cells.

Chen Q.-Y.,The 117th Hospital of PLA | Zheng Y.,Zhejiang Chinese Medical University | Zheng Y.,The 117th Hospital of PLA | Jiao D.-M.,The 117th Hospital of PLA | And 7 more authors.
Journal of Nutritional Biochemistry | Year: 2014

Curcumin, a natural and crystalline compound isolated from the plant Curcuma longa with low toxicity in normal cells, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about antimetastasis effects and mechanism of curcumin in lung cancer. Rac1 is an important small Rho GTPases family protein and has been widely implicated in cytoskeleton rearrangements and cancer cell migration, invasion and metastasis. In this study, we examined the influence of curcumin on in vitro invasiveness of human lung cancer cells and the expressions of Rac1. The results indicate that curcumin at 10 μM slightly reduced the proliferation of 801D lung cancer cells but showed an obvious inhibitory effect on epidermal growth factor or transforming growth factor β1-induced lung cancer cell migration and invasion. Meanwhile, we demonstrated that the suppression of invasiveness correlated with inhibition of Rac1/PAK1 signaling pathways and matrix metalloproteinase (MMP) 2 and 9 protein expression by combining curcumin treatment with the methods of Rac1 gene silence and overexpression in lung cancer cells. Laser confocal microscope also showed that Rac1-regulated actin cytoskeleton rearrangement may be involved in anti-invasion effect of curcumin on lung cancer cell. At last, through xenograft experiments, we confirmed the connection between Rac1 and the growth and metastasis inhibitory effect of curcumin in vivo. In summary, these data demonstrated that low-toxic levels of curcumin could efficiently inhibit migration and invasion of lung cancer cells through inhibition of Rac1/PAK1 signaling pathway and MMP-2 and MMP-9 expression, which provided a novel insight into the molecular mechanism of curcumin against lung cancer. © 2014 Elsevier Inc.

PubMed | Zhejiang Sci-Tech University, Peter MacCallum Cancer Center, Zhejiang Province Peoples Hospital, the 117th Hospital of PLA and Institute of Health science
Type: | Journal: Scientific reports | Year: 2016

LF11-322 (PFWRIRIRR-NH2) (PFR peptide), a nine amino acid-residue peptide fragment derived from human lactoferricin, possesses potent cytotoxicity against bacteria. We report here the discovery and characterization of its antitumor activity in leukemia cells. PFR peptide inhibited the proliferation of MEL and HL-60 leukemia cells by inducing cell death in the absence of the classical features of apoptosis, including chromatin condensation, Annexin V staining, Caspase activation and increase of abundance of pro-apoptotic proteins. Instead, necrotic cell death as evidenced by increasing intracellular PI staining and LDH release, inducing membrane disruption and up-regulating intracellular calcium level, was observed following PFR peptide treatment. In addition to necrotic cell death, PFR peptide also induced G0/G1 cell cycle arrest. Moreover, PFR peptide exhibited favorable antitumor activity and tolerability in vivo. These findings thus provide a new clue of antimicrobial peptides as a potential novel therapy for leukemia.

Wang R.,Bengbu Medical College | Li Y.,Bengbu Medical College | Hou Y.,Bengbu Medical College | Yang Q.,Bengbu Medical College | And 7 more authors.
Oncotarget | Year: 2015

Emerging evidence demonstrates that platelet-derived growth factor-D (PDGF-D) plays a critical role in epithelial-mesenchymal transition (EMT) and drug resistance in hepatocellular carcinoma (HCC) cells. However, the underlying mechanism has not been fully elucidated. The objective is to explore the molecular mechanism of PDGF-D-mediated EMT in drug resistance HCC cells. To achieve our goal, we used multiple approaches including Western blotting, real-time RT-PCR, wound healing assay, invasion assay, luciferase activity assay, transfection, and immunohistochemistry. We found that PDGF-D is highly expressed in gemcitabine-resistant (GR) HCC cells. Moreover, PDGF-D markedly inhibited miR-106a expression and subsequently upregulated Twist1 expression. Notably, PDGF-D expression was associated with miR-106a and Twist1 in HCC patients. Our findings provide a possible molecular mechanism for understanding GR chemoresistance in HCC cells. Therefore, inactivation of PDGF-D/Twist or activation of miR-106a could be a novel strategy for the treatment of HCC.

PubMed | Nanjing University and The 117th Hospital of PLA
Type: Journal Article | Journal: The European journal of neuroscience | Year: 2016

Bradykinin receptors play important roles in cerebral ischaemia-reperfusion (I/R) injury of non-diabetics. Their functions in diabetics, however, have not been studied. In this study, we hypothesized that bradykinin 1 receptor (B1R) and bradykinin 2 receptor (B2R) would be upregulated and participate in the regulation of diabetic ischaemic stroke. To investigate this, we first evaluated B1R and B2R expression at different time points after I/R in non-diabetic and diabetic rats (Sprague-Dawley) by using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence. Then, pharmacological inhibitors were separately administered via the tail vein to analyse their effects on cerebral ischaemia in diabetics. Both receptors were significantly upregulated after cerebral I/R in non-diabetic and diabetic rats. B1R expression in diabetic rats increased in a sharper manner than in non-diabetic rats, whereas B2R expression increased to the same level during the early stage of reperfusion but later became lower. Interestingly, the upregulated B1R was expressed in astrocytes, whereas B2R was mainly located in neurons in the ischaemic penumbra. Functional studies showed that inhibition of B1R significantly reduced infarct volume, neurological deficits, cell apoptosis, and neuron degeneration, probably by attenuating blood-brain barrier (BBB) disruption and post-ischaemic inflammation, at 24h after reperfusion. In contrast, B2R antagonist had opposite effects, and exacerbated BBB penetrability and tissue inflammation. These findings suggest that B1R and B2R have detrimental and beneficial effects, respectively in diabetic cerebral ischaemia, which might open new avenues for the treatment of ischaemic stroke in diabetic patients through selective pharmacological blockade or activation.

Chen Q.Y.,The 117th Hospital of PLA
Zhonghua zhong liu za zhi [Chinese journal of oncology] | Year: 2010

To detect the expression of alpha-tubulin and MDR1 in human non-small cell lung carcinoma (NSCLC), and to clarify their clinical significance. Paraffin embedded tissues from 158 primary non-small lung carcinomas and 30 paracancerous lung tissues were examined for expression of alpha-tubulin and MDR1 by immunohistochemistry (SP method). 30 freshly taken NSCLC tissues were examined by Western blot analysis. The relationship between alpha-tubulin and MDR1 expression and the biological features of lung carcinoma was analyzed. The positive rate of alpha-tubulin and MDR1 expressions in the lung carcinomas was 65.2% and 51.3%, respectively. There was no expression of either of them in 30 paracancerous lung tissues. Western blot analysis showed that the level of alpha-tubulin and MDR1 expressions in NSCLC tissues were 0.49 +/- 0.06 and 0.56 +/- 0.04, respectively, significantly higher than that in paracancerous tissues (0.07 +/- 0.01) (t = 3.693 and t = 6.769, P < 0.01). The positive rate of alpha-tubulin expression was gradually increased with tumor progression, significantly higher in III-IV stage cancers and in poorly differentiated carcinomas (both P < 0.01). There was a distinct statistically significant difference between stage I, stage II and III, and stage IV. The positive rate of alpha-tubulin in well-moderately differentiated carcinomas was lower than that in poorly differentiated ones. There was no significant correlation with age, sex, tumor size, histological type, clinical TNM system and lymph node metastasis. The positive rate of MDR1 was not correlated with sex, age, tumor size, pathological grading, clinical TNM stages and lymph node metastasis. But the positive rate of MDR1 in adenocarcinoma was significantly higher than that in squamous carcinoma and undifferentiated large cell carcinomas (P < 0.01). alpha-tubulin and MDR1 expression had no impact on the outcome of chemotherapy (chi(2) = 0.69 and 1.30, P > 0.05, respectively). Univariate analysis showed that the 5-year survival rate of patients with negative alpha-tubulin and MDR1 expression was 30.7% and 28.5%, respectively, significantly higher than that of patients with positive alpha-tubulin and MDR1 expression (13.5% and 11.8%, respectively) (chi(2) = 20.69 and 15.52, P < 0.01, respectively), and multivariate Cox regression analysis showed that alpha-tubulin (RR = 3.287, P = 0.006) and clinical TNM stage (RR = 1.954, P = 0.025) were significantly independent predictive factor for patients with lung cancer, MDR1 and other factors could not be used as an independent predicitive factors. However, there was no significant correlation between the expression of alpha-tubulin and MDR1 in lung carcinoma(r = 0.093, P > 0.05). The expression of alpha-tubulin and MDR1 may play an important role in the development and progression of human non-small cell lung carcinoma. Combined detection could be considered as an important index for predicting prognosis of lung carcinoma.

Chen Q.-Y.,The 117th Hospital of PLA | Jiao D.-M.,The 117th Hospital of PLA | Wang J.,The 117th Hospital of PLA | Hu H.,The 117th Hospital of PLA | And 4 more authors.
Oncotarget | Year: 2016

MicroRNAs (miRNAs) play a critical role in drug resistance and epithelialmesenchymal transition (EMT). The aims of this study were to explore the potential role of miR-206 in governing cisplatin resistance and EMT in lung cancer cells. We found that both lung adenocarcinoma A549 cisplatin-resistant cells (A549/DDP) and H1299 cisplatin-resistant cells (H1299/DDP) acquired mesenchymal features and were along with low expression of miR-206 and high migration and invasion abilities. Ectopic expression of miR-206 mimics inhibited cisplatin resistance, reversed the EMT phenotype, decreased the migration and invasion in these DDP-resistant cells. In contrast, miR-206 inhibitors increased cisplatin resistance, EMT, cell migration and invasion in non-DDP-resistant cells. Furthermore, we found that MET is the direct target of miR-206 in lung cancer cells. Knockdown of MET exhibited an EMT and DDP resistant inhibitory effect on DDP-resistant cells. Conversely, overexpression of MET in non-DDP-resistant cells produced a promoting effect on cell EMT and DDP resistance. In lung adenocarcinoma tissues, we demonstrated that low expression of miR-206 were also correlated with increased cisplatin resistance and MET expression. In addition, we revealed that miR-206 overexpression reduced cisplatin resistance and EMT in DDP-resistant cells, partly due to inactivation of MET/PI3K/AKT/mTOR signaling pathway, and subsequent downregulation of MDR1, ZEB1 and Snail expression. Finally, we found that miR-206 could also sensitize A549/DDP cells to cisplatin in mice model. Taken together, our study implied that activation of miR-206 or inactivation of its target gene pathway could serve as a novel approach to reverse cisplatin resistance in lung adenocarcinomas cells.

Zhang Z.J.,the 117th Hospital of PLA
Zhongguo gu shang = China journal of orthopaedics and traumatology | Year: 2012

To evaluate clinical results of an interspinous stabilization system (Wallis) in treating lumbar degenerative disease in the short-term. From August 2007 to June 2010,48 patients with lumbar degenerative disease who were treated with interspinous stabilization system, the data of patients were analyzed retrospectively. In all of the 48 cases, there were 30 males and 18 females with an average age of 54.2 years (ranged, 40 to 68 years). Forty-four cases were with single segment and 4 cases with two segments. Of them, 4 cases were in L3, 4, 40 cases were in L4, 5, 4 cases were in L3, 4 and L4, 5. The radiographic data of patients were analyzed. Clinical effects were evaluated by Japanese Orthopedic Association (JOA) score system and low back pain disability questionnaire (Oswestry) and Odom method. All the patients were followed up from 1 to 2 years with an average of 18 months. According to Odom's criteria, 20 cases obtained excellent results, 24 good, 4 fair. JOA score increased from 12.4 +/- 2.7 preoperatively to 26.1 +/- 2.0 postoperatively (P < 0.01). Oswestry score decreased from 14.1 +/- 2.9 preoperatively to 5.5 +/- 1.8 postoperatively (P < 0.01). The posterior height of intervertebral space and height of nerve root canal increased compared with that of preperative height. The treatment of lumbar degenerative disease with interspinous stabilization system can obtain satisfactory effects in the near future. It can retain dynamic stable of corresponding segments, expand volume of vertebral canal, and is safe and feasible.

Lou S.,The 117th Hospital of PLA | Zhao Z.,The 117th Hospital of PLA | Qian J.,The 117th Hospital of PLA | Zhao K.,The 117th Hospital of PLA | Wang R.,The 117th Hospital of PLA
International Journal of Clinical and Experimental Pathology | Year: 2014

Objective: Genetic factors play an important role in osteoarthritis (OA) etiology and ADAM12 gene polymorphisms may be involved. This study tried to examine the single-nucleotide polymorphisms (SNPs) of ADAM12 for their association with knee OA susceptibility in a Chinese Han population. Methods: The rs3740199, rs1871054, rs1278279, and rs1044122 SNPs in ADAM12 gene were genotyped in 152 subjects who were diagnosed as knee osteoarthritis and in 179 healthy controls. Results: Rs1871054 was found to be significantly associated with increased risk of OA (C vs. T, OR 1.802 (1.308 to 2.483), P < 0.0001) after adjustment of age, gender, and BMI. For other SNPs, no statistically significant associations with OA were found. Conclusion: In conclusion, our data demonstrated the ADAM12 rs1871054 variant was found to be significantly associated with increased OA susceptibility in a Chinese Han population.

PubMed | The 117th Hospital of PLA
Type: Journal Article | Journal: Oncology reports | Year: 2016

Lung cancer is the most common malignancy worldwide. This study aimed to identify miRNA biomarkers of lung adenocarcinoma and to investigate their molecular mechanisms. miRNA expression profiling of tumor tissues and adjacent normal tissues from 10patients were detected using microarray. Differentially expressed miRNAs (DEMs) were identified, and were verified using quantitative reverse transcription-PCR. Thereafter, correlations between DEM expression and clinicopathological features were determined in 49patients. Furthermore, Targetscan was utilized to predict target genes, among which transcription factors (TFs) were identified. The interactions among miRNAs, TFs and target genes were used to construct an miRNA-TF-target network. Totally, 11DEMs were identified, among which two downregulated miRNAs (miR-126-3p and miR-451a) were validated. Low levels of miR-126-3p and miR-451a were associated with poor pathological stage, large tumor diameter and lymph node metastasis (P<0.05). Receiver operating characteristic analysis showed that both miRNAs could predict pathological stage, tumor diameter and lymph node metastasis of lung adenocarcinoma (AUC >0.65, P<0.05). For miR-126-3p, 154 target genes were predicted (e.g., PLXNB2), which were enriched in 29pathways mainly concerning apoptosis and cancer. For miR451a, 397target genes were predicted, which were enriched in 5pathways including PPAR signaling pathway. Ten genes were co-regulated by miR-126-3p and miR-451a, e.g., TSC1. Furthermore, an miRNA-TF-target network was constructed, and a sub-network was identified, including 2miRNAs, 15targets, and 7TFs. In conclusion, miR-126-3p and miR-451a predicted the severity of lung adenocarcinoma. However, the possible mechanisms explored by bioinformatics need to be further validated.

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