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PubMed | Xi'an Jiaotong University, Shanxi Province Peoples Hospital and Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: International journal of oncology | Year: 2016

Aberrant expression of microRNA-155 (miR-155) has been reported in several human cancers and is associated with prognosis of patients. However, the clinical significance of miR155 and its underlying mechanisms involved in hepatocarcinogenesis remain to be determined. In this study, we demonstrated that the expression of miR-155 was elevated in both hepatocellular carcinoma (HCC) tissues and cell lines. Clinical association analysis revealed that high expression of miR-155 was correlated with malignant clinicopathological characteristics including large tumor size, high Edmondson-Steiner grading and TNM tumor stage. Furthermore, its high expression conferred a reduced 5-year overall survival and disease-free survival of HCC patients. Gain- and loss-of function studies revealed that miR155 promoted cell cycle progression, cell proliferation and inhibited apoptosis. Mechanistically, we identified AT-rich interactive domain 2 (ARID2) as a direct downstream target and functional mediator of miR155 in HCC cells. Notably, alterations of ARID2 expression abrogated the effects of miR155 on HCC cell proliferation, cell cycle and apoptosis. Moreover, we demonstrated that Akt phosphorylation is essential for the functional roles of miR155 through altering CyclinD1 and p27, which were key components of cell cycle machinery. Finally, we disclosed that the downregulation of miR155 suppressed tumor growth of HCC by inhibiting Akt signaling pathway. In conclusion, our results indicate that miR155 promotes tumor growth of HCC by targeting ARID2-mediated Akt phosphorylation pathway, and potentially serves as a novel prognostic biomarker and therapeutic target for HCC.

PubMed | The Center Hospital of Xian, Xi'an Jiaotong University and Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: Oncology reports | Year: 2016

Cancer stem cells (CSCs) are responsible for cancer progression and patient prognosis. Tripartite motif 16 (TRIM16) is a proteasome coactivator that regulates proteolytic activity in eukaryotic cells. Abundant evidence has shown that TRIM16 is lowly expressed in a number of human carcinomas. In a previous study, we demonstrated that TRIM16 suppressed cancer malignancy and that TRIM16 expression levels were associated with favorable prognostic parameters of patients with cancer. However, the precise role of this motif in the pathogenesis of breast cancer remains unknown. In the present study, we examined 29 human breast cancer specimens, and found that TRIM16 was lowly expressed in breast cancers; thus, TRIM16 expression is negatively correlated with metastasis in breast cancer patients. Moreover, we showed that TRIM16 suppressed CSC properties in a population of breast cancer cells. TRIM16 depletion resulted in an increased proportion of CSCs relative to breast cancer cells when several assays were used to assess CSC properties. Finally, we demonstrated that TRIM16 directly regulated the degradation of Gli1 protein via the ubiquitinproteasome pathway. In conclusion, we propose that inhibition of CSC properties may be one of the functions of TRIM16 as a suppressor of breast cancer progression.

Wang L.-J.,Xi'an Jiaotong University | He C.-C.,Xi'an Jiaotong University | Sui X.,Xi'an Jiaotong University | Cai M.-J.,Xi'an Jiaotong University | And 8 more authors.
Oncotarget | Year: 2015

Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR- 21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC.

Wu L.,Xi'an Jiaotong University | Wu L.,Shaanxi Provincial Tumor Hospital | Hui H.,Shaanxi Provincial Tumor Hospital | Wang L.-J.,Xi'an Jiaotong University | And 4 more authors.
Oncology Reports | Year: 2015

Accumulating evidence has demonstrated that microRNAs (miRNAs) are involved in multiple processes in cancer development and progression. miR-326 has been identified as a tumor suppressor miRNA in several types of human cancer. However, the specific function of miR-326 and its target the nin one binding protein (NOB1) in colorectal carcinoma (CRC) remains unclear. In the present study, we found that miR-326 inhibited cell proliferation, migration and invasion, and induced cell apoptosis and cell cycle arrest of CRC cells by directly targeting NOB1. Furthermore, the upregulation of miR-326 in CRC cells was revealed to be associated with a feedback loop involving downregulation of the NOB1, which mimics the phenotype induced by miR-326. Importantly, we found that the CRC patients with high expression of miR-326 or low expression of NOB1 tend to obtain a better prognosis. Thus, for the first time, we provide convincing evidence that downregulation of miR-326 inhibited tumor proliferation and tumor metastasis by directly targeting NOB1 in CRC. NOB1 and miR-326 could be potential therapeutic targets for CRC.

PubMed | Xi'an Jiaotong University and Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

Metastasis is one of the main causes of breast cancer (BCa)-related deaths in female. It has been reported that cancer stem cell played an important role in metastasis. Here we first revealed a specific role of pyruvate kinase isozymes M2 (PKM2) in the stemness of breast cancer cells. Breast cancer tissue analysis confirmed the upregulation of PKM2 in breast cancer, and high PKM2 levels were associated with poor prognosis of breast cancer patients. Holoclone assay and colony formation assay significantly elucidated the role of PKM2 in the self-renewal of breast cancer cells. Moreover, PKM2 elevated the proportion of stem cell and the ability of sphere formation in breast cancer cells. PKM2 played its functional role in stemness by regulating -catenin. Collectively, we identified critical roles of PKM2 in the stemness of breast cancer cells which may elevate the therapeutic effect on breast cancer patients.

PubMed | Xi'an Jiaotong University and Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: Experimental lung research | Year: 2016

This study investigated whether sarpogrelate hydrochloride (SPG), a 5-HT2A receptor antagonist, alleviates chronic hypoxic pulmonary hypertension (CH-PH) in rats by stimulating apoptosis and inhibiting proliferation in pulmonary artery smooth muscle cells (PASMCs).Forty male Sprague-Dawley rats were pretreated with SPG (50mg/kg/day by oral gavage) or saline vehicle and then subjected to chronic hypoxia (CH) (hypobaric chamber set to 380mmHg, 10% oxygen) or normoxia for 14days. Mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodeling was assayed by light microscopy. Terminal deoxynucletidyl transferase dUTP nick end ligase (TUNEL) assays, western blotting, and real-time polymerase chain reaction were used to assess apoptosis, proliferation and underlying signaling pathways in PASMCs from lung tissue and isolated pulmonary artery rings.CH increased mean PAP and RVH. CH increased the percentage of muscularized arteries in the peripheral pulmonary vasculature and medial wall thickness in small muscular arteries. CH increased pulmonary protein and mRNA levels of the B-cell lymphoma protein 2 (Bcl-2), pyruvate dehydrogenase kinase (PDK), phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2), cyclin D1, proliferating cell nuclear antigen (PCNA) and decreased protein and mRNA levels of Bcl-2-associated X protein (BAX), cleaved caspase-3. Pretreatment with SPG, which has been shown previously to inhibit ERK1/2 phosphorylation and PDK, countered all of these effects. Isolated pulmonary artery rings incubated with 5-HT increased pERK1/2, PDK, and Bcl-2 expression, and decreased Bax expression.Administration of SPG ameliorated the development of CH-PH by stimulating apoptosis in and inhibiting proliferation of PASMCs.

PubMed | National Engineering Research Center for Miniaturized Detection Systems, Northwest University, China and Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: Oncotarget | Year: 2016

Previous studies suggested that single nucleotide polymorphisms (SNPs) in epidermal growth factor receptor (EGFR) are associated with risk of glioma. However, the associations between these SNPs and glioma patient prognosis have not yet been fully investigated. Therefore, the present study was aimed to evaluate the effects of EGFR polymorphisms on the glioma patient prognosis. We retrospectively evaluated 269 glioma patients and investigated associations between EGFR SNPs and patient prognosis using Cox proportional hazard models and Kaplan-Meier curves. Univariate analysis revealed that age, gross-total resection and chemotherapy were associated with the prognosis of glioma patients (p < 0.05). In addition, four EGFR SNPs (rs11506105, rs3752651, rs1468727 and rs845552) correlated with overall survival (OS) (Log-rank p = 0.011, 0.020, 0.008, and 0.009, respectively) and progression-free survival PFS (Log-rank p = 0.026, 0.024, 0.019 and 0.009, respectively). Multivariate analysis indicated that the rs11506105 G/G genotype, the rs3752651 and rs1468727 C/C genotype and the rs845552 A/A genotype correlated inversely with OS and PFS. In addition, OS among patients with the rs730437 C/C genotype (p = 0.030) was significantly lower OS than among patients with A/A genotype. These data suggest that five EGFR SNPs (rs11506105, rs3752651, rs1468727, rs845552 and rs730437) correlated with glioma patient prognosis, and should be furthered validated in studies of ethnically diverse patients.

Yang L.Q.,The Second Affiliated Hospital Of Xian Medical University | Zhang Y.,Chinese Academy of Sciences | Sun H.F.,Shaanxi Provincial Tumor Hospital
Genetics and Molecular Research | Year: 2016

Our study aimed to investigate the role of 2 ERCC5 promoter SNPs (rs2094258 and rs751402) in the development of gastric cancer in the Chinese population. The present hospital-based case-control study consisted of 155 patients with gastric cancer and 246 healthy controls recruited between March 2012 and December 2014. Genotyping for the rs2094258 and rs751402 polymorphic sites was carried out using polymerase chain reaction-restriction fragment length polymorphism. Statistical analyses were conducted using the SPASS version 16.0 software (SPSS, Inc., Chicago, IL, USA). As determined by the chi-square test, there was a significant difference in the genotype distributions of rs751402 between patients and controls (χ2 = 6.74, P = 0.03). By unconditional logistic regression analysis, we observed that the TT genotype in rs751402 was significantly associated with increased risk to gastric cancer as compared with the CC genotype, and the adjusted OR (95%CI) was 2.17 (1.15-4.09). Moreover, subjects carrying the T allele in rs751402 had elevated risk of developing gastric cancer when compared with those carrying the C allele, with an adjusted OR value (95%CI) of 1.47 (1.09-1.99). In conclusion, we suggest that the ERCC5 rs751402 gene polymorphism may influence the susceptibility to gastric cancer in the Chinese population. © 2016 The Authors.

PubMed | Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: Genetics and molecular research : GMR | Year: 2016

The aim of this study was to examine the subtype distribution of human papilloma virus (HPV) in women in the Shaanxi Province of China. A DNA chip, along with polymerase chain reaction amplification and reverse dot blot technology, was adopted to analyze the HPV genotypes of 22,937 cases of cervical cell specimens. The HPV infection rate was 18.70%, wherein high-risk, low-risk, and high- and low-risk multiple infection rates were 15.75, 2.96 and 1.91%, respectively. High-risk infections accounted for 84.20% of total infections. The rate of HPV infection in women with rural residence, high school education or less, a low income, or age over 40 years was significantly higher than that in the control group (negative HPV infection women). Of the 18 detected high-risk HPV subtypes, the most common in single infections were, in the order of prevalence, HPV16, 58, 18, 52, 33, and 56. For multiple high-risk infections, the most common subtypes in the order of prevalence were HPV16, 52, 58, 18, 56, and 33. Age was a factor in the rate of infection, as the 41-50-year age group had a significantly higher risk of infection than the other groups (P < 0.05). In multiple infections, double infections were common, accounting for 77.10% of multiple infections, and triple or more infections were more common in women aged 51-60 years. In Shaanxi Province, high-risk HPV infection in women was mainly attributed to rural residence, age over 40 years, low income, and low education level.

PubMed | Shaanxi Provincial Tumor Hospital
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

Sphingosine kinase 1 (SphK1) expression is elevated in various cancers and is associated with shorter survival times for patients. However, the molecular mechanism of SphK1 up-regulation in triple-negative breast cancer (TNBC) remains unclear. In this study, we assayed the expression level of SphK1 in TNBC tissues by qRT-PCR and immunohistochemistry. The level of S1P was quantified by ELISA in the serum of TNBC patients. Our results found that the levels of SphK1 and S1P were significantly increased in TNBC patients compared with normal control. Furthermore, knockdown of SphK1 with siRNA decreased TNBC cell proliferation and inhibited cell migration/invasion. These data suggest that SphK1 has an important role in TNBC and presents an attractive therapeutic target for the treatment for TNBC.

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