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Shu-Mei Yan,
Jian-Jun Tang,
Chun-Yu Huang,
Shao-Yan Xi,
Ma-Yan Huang,
Jian-Zhong Liang,
Yuan-Xue Jiang,
Yu-Hong Li,
Zhi-Wei Zhou,
Ingemar Ernberg,
Qiu-Liang Wu, Zi-Ming Du
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ABSTRACT: BACKGROUND: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma. METHODOLOGYPRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001). CONCLUSIONSSIGNIFICANCE: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.
PLoS ONE 01/2013; 8(2):e56366. · 4.09 Impact Factor
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Jiang Li,
Hao-Yuan Mo,
Geng Xiong,
Lin Zhang,
Jia He,
Zhou-Feng Huang,
Zhi-Wei Liu,
Qiu-Yan Chen, Zi-Ming Du,
Li-Min Zheng,
Chao-Nan Qian,
Yi-Xin Zeng
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ABSTRACT: The accumulation of an intratumoral CD4(+) interleukin-17-producing subset (Th17) of tumor-infiltrating lymphocytes (TILs) is a general characteristic in many cancers. The relationship between the percentage of Th17 cells and clinical prognosis differs among cancers. The mechanism responsible for the increasing percentage of such cells in NPC is still unknown, as is their biological function. Here, our data showed an increase of Th17 cells in tumor tissues relative to their numbers in normal nasopharynx tissues or in the matched peripheral blood of NPC patients. Th17 cells in tumor tissue produced more IFNγ than did those in the peripheral blood of matched NPC patients and healthy controls. We observed high levels of CD154, G-CSF, CXCL1, IL-6, IL-8, and macrophage inhibitory factor (MIF) out of 36 cytokines examined in tumor tissue cultures. MIF promoted the generation and recruitment of Th17 cells mediated by NPC tumor cells in vitro; this promoting effect was mainly dependent on the mammalian target of rapamycin pathway and was mediated by the MIF-CXCR4 axis. Finally, the expression level of MIF in tumor cells and in TILs was positively correlated in NPC tumor tissues, and the frequency of MIF-positive TILs was positively correlated with NPC patient clinical outcomes. Taken together, our findings illustrate that tumor-derived MIF can affect patient prognosis, which might be related to the increase of Th17 cells in the NPC tumor microenvironment.
Journal of Biological Chemistry 08/2012; 287(42):35484-95. · 4.77 Impact Factor
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ABSTRACT: ULK1 plays an important role in autophagy which is widely involved in the development of breast cancer. However, the function and expression of ULK1 in human breast cancer is still scarcely explored. In this study, we showed that the mRNA and protein levels of ULK1 decreased in 10 of 14 (71.4 %) breast cancer tissues, compared with matched normal tissues. Furthermore, immunohistochemical staining of ULK1 was performed on the tissue microarray containing 298 non-metastatic invasive breast primary cancer tissues and 73 matched adjacent noncancerous tissues. 70.1 % breast cancer specimens displayed none to weak staining of ULK1, however, 78.1 % adjacent noncancerous specimens showed moderate to strong staining of ULK1. Statistical analysis revealed that ULK1 expression was negatively correlated with tumor size (r = -0.176, P = 0.002), lymph node status (r = -0.115, P = 0.048), and pathological stage (r = -0.177, P = 0.002). The log-rank test showed that patients with lower level of ULK1 had a significant shorter distant metastasis-free survival time (P = 0.008) and cancer-related survival time (P = 0.008). Multivariate Cox regression analysis found that ULK1 expression was recognized as an independent prognostic factor (P = 0.034). In addition, a significant positive correlation between expression of ULK1 and LC3A (r = 0.401, P < 0.001), and a significant negative correlation between expression of ULK1 and p62 (r = -0.226, P < 0.001) were observed in our breast cancer cohort. These findings suggest that decreased expression of ULK1 is associated with breast cancer progression, together with closely related to decreased autophagic capacity. ULK1 also may be used as a novel prognostic biomarker for breast cancer patients.
Breast Cancer Research and Treatment 05/2012; 134(2):549-60. · 4.43 Impact Factor
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Zi-Ming Du,
Chang-Wei Kou,
Hai-Yun Wang,
Ma-Yan Huang,
Ding-Zhun Liao,
Chun-Fang Hu,
Jing Chen,
Li-Xu Yan,
Li-Fu Hu,
Ingemar Ernberg,
Yi-Xin Zeng,
Jian-Yong Shao
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ABSTRACT: Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase and often aberrantly expressed in human cancers. However, Syk expression pattern has not yet been investigated in nasopharyngeal carcinoma (NPC).
Samples of 223 NPC tissues were immunohistochemically stained for Syk expression and survival analysis was then performed. Interaction and co-localization of Syk with Epstein-Barr virus encoded latent membrane protein 2A (LMP2A) was explored.
High expression of Syk was detected in 24% of NPC cases, and correlated significantly with T classification, local recurrence, a lower 5-year survival rate, and a lower 5-year disease-free survival (DFS) rate. Syk expression was a significant, independent prognosis predictor for patients with NPC. LMP2A induced Syk expression in NPC and LMP2A high expression correlated with Syk high expression in NPC clinical samples.
High expression of Syk, which results partly from LMP2A expression in NPC, is associated with tumor recurrence and poor prognosis of patients with NPC. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.
Head & Neck 01/2012; 34(10):1456-64. · 2.40 Impact Factor
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Hai-Yun Wang,
Bing-Yu Sun,
Zhi-Hua Zhu,
Ellen T Chang,
Ka-Fai To,
Jacqueline S G Hwang,
Hao Jiang,
Michael Koon-Ming Kam,
Gang Chen,
Shie-Lee Cheah, [......],
Ho-Keung Ng,
Joseph T S Wee,
Chao-Nan Qian,
Qing Liu,
Ingemar Ernberg,
Weimin Ye,
Hans-Olov Adami,
Anthony T Chan,
Yi-Xin Zeng,
Jian-Yong Shao
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ABSTRACT: Currently, nasopharyngeal carcinoma (NPC) prognosis evaluation is based primarily on the TNM staging system. This study aims to identify prognostic markers for NPC.
We detected expression of 18 biomarkers by immunohistochemistry in NPC tumors from 209 patients and evaluated the association between gene expression level and disease-specific survival (DSS). We used support vector machine (SVM)--based methods to develop a prognostic classifier for NPC (NPC-SVM classifier). Further validation of the NPC-SVM classifier was performed in an independent cohort of 1,059 patients.
The NPC-SVM classifier integrated patient sex and the protein expression level of seven genes, including Epstein-Barr virus latency membrane protein 1, CD147, caveolin-1, phospho-P70S6 kinase, matrix metalloproteinase 11, survivin, and secreted protein acidic and rich in cysteine. The NPC-SVM classifier distinguished patients with NPC into low- and high-risk groups with significant differences in 5-year DSS in the evaluated patients (87% v 37.7%; P < .001) in the validation cohort. In multivariate analysis adjusted for age, TNM stage, and histologic subtype, the NPC-SVM classifier was an independent predictor of 5-year DSS in the evaluated patients (hazard ratio, 4.9; 95% CI, 3.0 to 7.9) in the validation cohort.
As a powerful predictor of 5-year DSS among patients with NPC, the newly developed NPC-SVM classifier based on tumor-associated biomarkers will facilitate patient counseling and individualize management of patients with NPC.
Journal of Clinical Oncology 12/2011; 29(34):4516-25. · 18.37 Impact Factor
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Yan Zhang,
Li-Xu Yan,
Qi-Nian Wu, Zi-Ming Du,
Jing Chen,
Ding-Zhun Liao,
Ma-Yan Huang,
Jing-Hui Hou,
Qiu-Liang Wu,
Mu-Sheng Zeng,
Wen-Lin Huang,
Yi-Xin Zeng,
Jian-Yong Shao
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ABSTRACT: The microRNA miR-125b is dysregulated in various human cancers but its underlying mechanisms of action are poorly understood. Here, we report that miR-125b is downregulated in invasive breast cancers where it predicts poor patient survival. Hypermethylation of the miR-125b promoter partially accounted for reduction of miR-125b expression in human breast cancer. Ectopic restoration of miR-125b expression in breast cancer cells suppressed proliferation, induced G(1) cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo. We identified the ETS1 gene as a novel direct target of miR-125b. siRNA-mediated ETS1 knockdown phenocopied the effect of miR-125b in breast cell lines and ETS1 overexpression in invasive breast cancer tissues also correlated with poor patient prognosis. Taken together, our findings point to an important role for miR-125b in the molecular etiology of invasive breast cancer, and they suggest miR-125b as a potential theranostic tool in this disease.
Cancer Research 03/2011; 71(10):3552-62. · 7.86 Impact Factor
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ABSTRACT: The role of microRNA-155 (miR-155) has been associated with oncogenesis of several human tumors. However the expression pattern of miR-155 has not been investigated in nasopharyngeal carcinoma (NPC). The present study was to assess miR-155 expression pattern and its possible function in NPC, to identify its targets and evaluate their clinical applications in NPC. MiR-155 was found to be upregulated in two Epstein-Barr virus (EBV) negative NPC derived cell lines CNE1 and TW03, as well as in NPC clinical samples by quantitative Real-time PCR and in situ hybridization detection. EBV encoded LMP1 and LMP2A could further enhance the expression of miR-155 in NPC CNE1 and TW03 cells. JMJD1A and BACH1 were identified as putative targets of miR-155 in a bioinformatics screen. Overexpression of miR-155 downregulated a luciferase transcript fused to the 3'UTR of JMJD1A and BACH1. MiR-155 mimic could downregulate the expression of JMJD1A and BACH1, while miR-155 inhibitor could upregulate JMJD1A expression in NPC cell lines. Moreover, downregulation of JMJD1A was significantly correlated with N stage in TNM classification (p = 0.023), a lower five-year survival rate (p = 0.021), and a lower five-year disease-free survival rate (p = 0.049) of NPC patients. Taken together, up-regulation of miR-155 in NPC is partly driven by LMP1 and LMP2A, and results in downregulation of JMJD1A, which is associated with N stage and poor prognosis of NPC patients. The potential of miR-155 and JMJD1A as therapeutic targets in NPC should be further investigated.
PLoS ONE 01/2011; 6(4):e19137. · 4.09 Impact Factor
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ABSTRACT: Expression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) and their prognostic significance were analyzed in archive NPC samples. Cav-1 and CD147 were overexpressed in 49.48% (96/194) and 59.39% (117/197) of NPC, respectively. Both Cav-1 and CD147 expression levels correlated significantly with metastasis (p = 0.025 and 0.017, respectively) and a lower 5-year survival rate (p = 0.02 and 0.0009, respectively). In addition, Cav-1 expression levels correlated significantly with local recurrence (p = 0.038). Multivariate Cox regression analysis indicated that combination of high Cav-1 and CD147 expression was a significant, independent prognosis predictor in patients with NPC (HR = 2.135; p = 0.006). Functional studies revealed that overexpression of Cav-1 promoted secretion of MMP-3 and MMP-11 (active) proteins, as well as an increase in the migratory ability of CNE1 and CNE2 cells, while siRNA-mediated silencing of Cav-1 or CD147 led to reduced levels of MMP-3 and MMP-11(active) secretion, and reduced migration capacity of CNE1 and CNE2 cells. We observed a positive correlation between Cav-1 and CD147 expression in NPC (rho = 0.330, p = 0.000), CD147 protein levels were upregulated in Cav-1 overexpressing CNE1 and CNE2 cells, whereas siRNA-mediated silencing of Cav-1 led to the downregulation of CD147 expression. Our results indicate that Cav-1 and CD147 overexpression predict poor NPC prognosis and enhanced tumor cell migration, which is associated with MMP-3 and MMP-11 (active) secretion.
International Journal of Cancer 05/2009; 125(8):1832-41. · 5.44 Impact Factor
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[show abstract]
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ABSTRACT: Expression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) and their prognostic significance were analyzed in archive NPC samples. Cav-1 and CD147 were overexpressed in 49.48% (96/194) and 59.39% (117/197) of NPC, respectively. Both Cav-1 and CD147 expression levels correlated significantly with metastasis (p = 0.025 and 0.017, respectively) and a lower 5-year survival rate (p = 0.02 and 0.0009, respectively). In addition, Cav-1 expression levels correlated significantly with local recurrence (p = 0.038). Multivariate Cox regression analysis indicated that combination of high Cav-1 and CD147 expression was a significant, independent prognosis predictor in patients with NPC (HR = 2.135; p = 0.006). Functional studies revealed that overexpression of Cav-1 promoted secretion of MMP-3 and MMP-11 (active) proteins, as well as an increase in the migratory ability of CNE1 and CNE2 cells, while siRNA-mediated silencing of Cav-1 or CD147 led to reduced levels of MMP-3 and MMP-11(active) secretion, and reduced migration capacity of CNE1 and CNE2 cells. We observed a positive correlation between Cav-1 and CD147 expression in NPC (ρ = 0.330, p = 0.000), CD147 protein levels were upregulated in Cav-1 overexpressing CNE1 and CNE2 cells, whereas siRNA-mediated silencing of Cav-1 led to the downregulation of CD147 expression. Our results indicate that Cav-1 and CD147 overexpression predict poor NPC prognosis and enhanced tumor cell migration, which is associated with MMP-3 and MMP-11 (active) secretion. © 2009 UICC
International Journal of Cancer 04/2009; 125(8):1832 - 1841. · 5.44 Impact Factor
