Publications (19)82.27 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Various studies have evaluated the significance of Notch1 expression in breast cancer, but the results have ever been disputed. By using 21 studies involving 3867 patients, this meta-analysis revealed that the expression of Notch1 was significantly higher in breast cancer than in normal tissues (OR=7.21; 95%CI, 4.7-11.07) and that higher Notch1 expression was associated with transition from ductal carcinoma in situ (DCIS) to invasive cancer (OR=3.75; 95% CI, 1.8-7.78). Higher Notch1 activity was observed in the basal subtype of breast cancer (OR=2.53; 95% CI, 1.18-5.43). Moreover, patients with Notch1 overexpression exhibited significantly worse overall and recurrence-free survival. Our meta-analysis suggests that Notch inhibitors may be useful in blocking the early progression of DCIS and that the outcomes of clinical trials for Notch1-targeting therapeutics could be improved by the molecular stratification of breast cancer patients.
- [Show abstract] [Hide abstract] ABSTRACT: Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/β-catenin pathway in radiation-induced invasion of glioblastoma cells. U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/β-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of β-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/β-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of β-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography. U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of β-catenin. Moreover, we found increased β-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/β-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/β-catenin pathway by XAV 939, which promotes degradation of β-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases. Our data demonstrate a pivotal role of the Wnt/β-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting β-catenin is a promising therapeutic approach to overcoming glioma radioresistance.
- [Show abstract] [Hide abstract] ABSTRACT: Various studies have assessed the clinicopathological and prognostic value of Notch1 and Notch3 expression in Non-small cell lung cancer (NSCLC), but their results remain controversial. This meta-analysis was conducted to address the above issues by using a total of 19 studies involving 3663 patients. The correlations between Notch1 and Notch3 expression and clinicopathological features and NSCLC prognosis were analyzed. The meta-analysis indicated that higher expression of Notch1 was associated with greater possibility of lymph node metastasis and higher TNM stages. Moreover, patients with Notch1 overexpression and Notch3 overexpression showed significantly poor overall survival (Notch1: HR, 1.29; 95% CI, 1.06-1.57, p = 0.468 and I(2) = 0.0%; Notch3: HR, 1.57; 95%CI, 1.04-2.36, p = 0.445 and I(2) = 0.0%). Furthermore, there are statistically significant association between overall survival of NSCLC patients and the expression of Notch signaling ligand DLL3 and target gene HES1. Our meta-analysis supports that Notch signaling is a valuable bio-marker to predict progression and targeting Notch signaling could benefit subpopulation of NSCLC patients.
- [Show abstract] [Hide abstract] ABSTRACT: The cell fate determination factor Dachshund (DACH1) functions as a novel suppressor in the progression of various neoplasms. Previous study has suggested that hypermethylation of promoter region was responsible for the reduction of DACH1 expression in hepatocellular carcinoma (HCC), and associated with the progression of HCC, but the clinical significance and the exact molecular mechanisms of DACH1 in the progression of HCC remain unclear. In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression. Notably, Kaplan-Meier analysis further indicated DACH1 could be an independent prognostic factor for the overall survival of HCC. Further, mechanistic studies revealed that overexpression of DACH1 inhibited the growth and migration of HCC cell line, which were dependent in part on the inactivation of Wnt pathway via phosphorylation of GSK3β to suppress β-catenin. In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes. Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.
- [Show abstract] [Hide abstract] ABSTRACT: The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients. © 2015 UICC.
- [Show abstract] [Hide abstract] ABSTRACT: Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival.
- [Show abstract] [Hide abstract] ABSTRACT: Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung cancer (NSCLC). Correspondingly, blocking of Notch signaling inhibits NSCLC migration and tumor growth by reversing EMT. Clinical trials have showed promising effect in some cancer patients received treatment with Notch1 inhibitor. This review attempts to provide an overview of the Notch signal in NSCLC: its biological significance and therapeutic application.
- [Show abstract] [Hide abstract] ABSTRACT: Background The aim of the present study was to compare the clinical efficacy of radical nephrectomy (RN) with nephron-sparing surgery (NSS) in treating patients with localized renal cell carcinoma (RCC).Methods The literature search was performed in PubMed, MEDLINE Springer, Elsevier Science Direct, Cochrane Library, and Google Scholar up to December 2012. The software Review Manager 5.1 and the STATA software package v.11.0 were used for analyses. The odds ratios (ORs) and its 95% confidence interval (95% CI) were calculated for comparison. Subgroup analyses were performed based on the tumor size of RCC.ResultsIn total, 10 studies with 10,174 RCC patients (7,050 treated with RN and 3,124 treated with NSS) were selected. The pooled estimate (OR =1.58, 95% CI =1.15¿2.15, P =0.004) showed a significantly lower rate of cancer-specific deaths in the patients treated with NSS compared to RN. However, no statistically significant differences were found in the rate of tumor recurrence (OR =0.84, 95% CI =0.67¿1.06, P =0.14) and complications (OR =0.91, 95% CI =0.51¿1.63, P =0.74) between the patients treated with NSS and RN. In addition, all the subgroup analyses presented consistent results with the overall analyses.ConclusionsNSS had no significantly different from RN in tumor recurrence and complications for localized RCC. However, the significantly lower rate of cancer-specific deaths supported the use of NSS not only for RCC with tumor size >4.0 cm but also for tumor sizes ¿4.0 cm compared with RN.
- [Show abstract] [Hide abstract] ABSTRACT: Hyperthermia has long been used in combination with radiation for the treatment of cancers. This study aimed to investigate the efficacy safety and impact on the immune function of the abdominal hyperthermia combining with radiotherapy. Sixty-eight patients with post-operative local recurrent gastric carcinoma were divided randomly into two groups. Patients in 3DCRT+HT group received three-dimensional conformal radio therapy combined with abdominal hyperthermia while patients from 3DCRT group only received the three-dimensional conformal radiation therapy. The differences of efficacy, toxicity and the impact on immune function between two kinds of therapies were compared. Response rate in 3DCRT+HT group was 57.2%, which was significant higher than that in 3DCRT group (47.1%) (P=0.04). Median local progression-free survival time of 3DCRT+HT group (14 months) was significantly longer than 3DCRT group (11 months). The peripheral blood T lymphocyte subsets analyses showed that, after the treatment, CD3+, CD4+, NK level and CD4+/CD8+ ratio increased significantly, while there was no significant alterations for those immunological parameters in 3DCRT group. Abdominal hyperthermia combined with three-dimensional conformal radiotherapy could gain higher response rate, prolong median local progression-free survival time and improve immune function for the post-operative recurrentgastric cancer.
- [Show abstract] [Hide abstract] ABSTRACT: Background Renal cell carcinoma (RCC) is a complex with diverse biological characteristics and distinct molecular signature. New target therapies to molecules that drive RCC initiation and progression have achieved promising responses in some patients, but the total effective rate is still far from satisfaction. Dachshund (DACH1) network is a key signaling pathway for kidney development and has recently been identified as a tumor suppressor in several cancer types. However, its role in renal cell carcinoma has not been fully investigated.Methods Immunohistochemical staining for DACH1, PCNA and cyclin D1 was performed on human renal tissue microaraays and correlation with clinic-pathological characteristics was analyzed. In vitro proliferation, apoptosis and in vivo tumor growth were evaluated on human renal cancer cell lines with decitabine treatment or ectopic expression of DACH1. Downstream targets and potential molecular mechanism were investigated through western blot, immunoprecipitation and reporter gene assays.ResultsExpression of DACH1 was significantly decreased in human renal carcinoma tissue. DACH1 protein abundance was inversely correlated with the expression of PCNA and cyclin D1, tumor grade, and TNM stage. Restoration of DACH1 function in renal clear cell cancer cells inhibited in vitro cellular proliferation, S phase progression, clone formation, and in vivo tumor growth. In mechanism,DACH1 repressed cyclin D1 transcription through association with AP-1 protein.Conclusion Our results indicated that DACH1 was a novel molecular marker of RCC and it attributed to the malignant behavior of renal cancer cells. Re-activation of DACH1 may represent a potential therapeutic strategy.
- [Show abstract] [Hide abstract] ABSTRACT: The effects of connective tissue growth factor (CTGF) gene silencing on the radiosensitivity of glioblastoma cells (GBM) were investigated. The lentivirus-mediated short hairpin RNA (shRNA) expression vector targeting CTGF was constructed and transinfected into U87MG human GBM cell line. The CTGF gene expression in U87MG cells was significantly down-regulated. After irradiation with 6 MV X-rays at a dose rate of 2.5 Gy/min, the clonogenicity, proliferation and migration of U87MG cells were assayed in vitro. The survival, proliferation and migration of U87MG cells were all remarkably inhibited by CTGF silencing (p < 0.05 vs control). Our results demonstrate that CTGF is important for GBM and CTGF gene silencing can be a potential tool to enhance the sensitivity of GBM to radiotherapy.
- [Show abstract] [Hide abstract] ABSTRACT: Radioresistance remains a significant therapeutic obstacle in glioblastoma. Reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation and apoptosis. Nox4 NADPH oxidase is abundantly expressed and has proven to be a major source of ROS production in glioblastoma. Here we investigated the effects of Nox4 on GBM tumor cell invasion, angiogenesis, and radiosensitivity. A lentiviral shRNA vector was utilized to stably knockdown Nox4 in U87MG and U251 glioblastoma cells. ROS production was measured by flow cytometry using the fluorescent probe DCFH-DA. Radiosensitivity was evaluated by clonogenic assay and survival curve was generated. Cell proliferation activity was assessed by a cell counting proliferation assay and invasion/migration potential by Matrigel invasion assay. Tube-like structure formation assay was used to evaluate angiogenesis ability in vitro and VEGF expression was assessed by MTT assay. Nox4 knockdown reduced ROS production significantly and suppressed glioblastoma cells proliferation and invasion and tumor associated angiogenesis and increased their radiosensitivity in vitro. Our results indicate that Nox4 may play a crucial role in tumor invasion, angiogenesis, and radioresistance in glioblastoma. Inhibition of Nox4 by lentivirus-mediated shRNA could be a strategy to overcome radioresistance and then improve its therapeutic efficacy for glioblastoma.
- [Show abstract] [Hide abstract] ABSTRACT: Heterogeneous ribonucleoproteins (hnRNPs) are involved in a variety of key cellular functions and are most likely involved in different steps of pre-mRNA processing. Over the past decades, the central roles of hnRNPs have been detected, which show that they are involved in RNA splicing, telomere biogenesis, DNA repair, cell signaling, and in transcription and translation. Mounting evidence suggests that they are involved in the regulation of mRNA stability and translation in many cancer types. The hnRNPs have a variety of potential roles in inhibition of apoptosis, angiogenesis, cell invasion, and epithelial-mesenchymal transition (EMT). It is thus suggested that hnRNP might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation. The aims of this review are to survey the existing evidence and discuss the diverse functions of hnRNPs in cancer metastasis.
- [Show abstract] [Hide abstract] ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are being widely used as targeted therapy in non-small cell lung cancer (NSCLC), but most cases acquire drug-resistance in 9 months. However, the mechanisms of resistance are still not fully understood. Since it has been demonstrated that EGFR-TKI-mediated repression of downstream signaling cascades and apoptosis induction is a key mechanism through which EGFR-TKIs exert their cytotoxic effects, we reasoned that activation of downstream signaling pathways and changes in the expression of apoptosis-related proteins contribute to the acquired resistance to EGFR-TKIs. We analyzed the protein levels of p-Akt, Bcl-2, Bax between gefitinib-sensitive and gefitinib-resistant lung cancer cell lines and evaluated whether targeting the anti-apoptotic protein Bcl-2 induces cell apoptosis and further sensitizes resistant H1975 cells to gefitinib. The data showed that p-Akt was activated and accompanied by substantial Bcl-2 in the H1975 lung cancer cell line, whereas no evidence was observed in HCC827 cells. Using small interfering RNA (siRNA) to silence Bcl-2 in H1975 cells led to significant downregulation of Bcl-2 protein expression, decreased cell viability in vitro and induced intrinsic apoptosis confirmed by flow cytometry and PARP cleavage. In Bcl-2 siRNA-transfected cells, adding gefitinib further reduced the number of viable cells, induced apoptosis to a greater extent compared to either treatment alone. These preclinical data suggested that downregulation of Bcl-2 by RNAi in the gefitinib-resistant H1975 lung cancer cell line with T790M mutation enhanced the effects of gefitinib and may offer a novel therapeutic strategy for the treatment of NSCLC.
- [Show abstract] [Hide abstract] ABSTRACT: Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFβR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFβR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma.
- [Show abstract] [Hide abstract] ABSTRACT: Here we investigate the effects of the novel transforming growth factor-β receptor I (TGF-βRI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated MGMT promoter), and endothelial cells (HUVECs) were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67) and the microvessel density (CD31 count), the relative pericyte coverage (α-SMA/CD31 ratio) increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-βRI kinase inhibitor to the present clinical standard (radiation plus TMZ) has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status.
- [Show abstract] [Hide abstract] ABSTRACT: To construct a CXCR4 specific recombinant plasmid vector and study its inhibiting effect on invasion capacity in vitro of human breast cancer MDA-MB-231 cell line and its metastatic potential to the lung in nude mice. A CXCR4 specific recombinant plasmid vector was constructed and transfected into the cultured MDA-MB-231 cell line with lipofectamine 2000. RT-PCR and Western blot were used to detect the mRNA and protein expression of CXCR4, respectively. Invasion capability in vitro of the cells was evaluated by Boyden chamber. The cell proliferation capacity was detected by MTT method. The nude mouse model of lung metastasis was established by injection of MDA-MB-231 cells into the tail vein. The animals were sacrificed at 6 weeks after the tumor cells injection. Whole lung tissues were harvested, embedded in paraffin, sectioned serially, and the HE-stained paraffin sections were examined pathologically to evaluate the presence and number of metastatic tumors. The CXCR4 mRNA expression rate was 29.5% +/- 3.8% in the CXCR4-shRNA group, significantly lower than that of the control group (69.7% +/- 2.6%, P < 0.01) and mock-control group (67.8% +/- 3.5%, P < 0.01). The CXCR4 protein expression rate was 15.4% +/- 1.1% in the CXCR4-shRNA group, significantly lower than that of the control group (39.0% +/- 2.4%, P < 0.01) and mock-control group (35.9% +/- 3.9%, P < 0.01). Silencing of CXCR4 by shRNA lead to a significant decrease in breast cancer cell invasion and proliferation capacity in vitro. Furthermore, tumor cells with CXCR4 shRNA permanent transfcetion had a much lower lung metastatic potential in nude mice than control cells and mock control cells in vivo. CXCR4 shRNA can inhibit the expression of CXCR4 and decrease the invasion and lung metastatic potential of human breast cancer cells.
Huazhong University of Science and TechnologyWu-han-shih, Hubei, China