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Yan Li Cai-Lei Zhu Chang-Jun Nie Jiang-Chao Li Ting-ting Zeng Jie Zhou Jinna Chen Kai Chen Li Fu Haibo Liu Yanru Qin Xin-Yuan Guan 《PloS one》2013,8(4)
Background
Deletion of 3p is one of the most frequent genetic alterations in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes (TSGs) within these regions. In this study, one TSG, CACNA2D3 at 3p21.1, was characterized.Methods
Expression of CACNA2D3 in ESCCs was tested by quantitative real-time PCR and tissue microarray. The mechanism of CACNA2D3 downregulation was investigated by methylation-specific polymerase chain reaction (MS-PCR). The tumor suppressive function of CACNA2D3 was characterized by both in vitro and in vivo tumorigenic assays, cell migration and invasion assays.Results
CACNA2D3 was frequently downregulated in ESCCs (24/48, 50%), which was significantly associated with promoter methylation and allele loss (P<0.05). Tissue microarray result showed that downregulation of CACNA2D3 was detected in (127/224, 56.7%) ESCCs, which was significantly associated with lymph node metastasis (P = 0.01), TNM staging (P = 0.003) and poor outcome of ESCC patients (P<0.05). Functional studies demonstrated that CACNA2D3 could inhibit tumorigenicity, cell motility and induce apoptosis. Mechanism study found that CACNA2D3 could arrest cell cycle at G1/S checkpoint by increasing expressions of p21 and p53 and decreasing expression of CDK2. In addition, CACNA2D3 could upregulate intracellular free cytosolic Ca2+ and subsequently induce apoptosis.Conclusion
CACNA2D3 is a novel TSG responsible to the 3p21 deletion event and plays a critical suppressing role in the development and progression of ESCC. 相似文献2.
Jian Ming Hu Ling Li Yun Zhao Chen Chunxia Liu Xiaobin Cui Liang Yin Lan Yang Hong Zou Lijuan Pang Jin Zhao Yan Qi Yuwen Cao Jinfang Jiang Weihua Liang Feng Li 《Epigenetics》2014,9(10):1366-1373
Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC. 相似文献
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Jianming Hu Ling Li Lijuan Pang Yunzhao Chen Lan Yang Chunxia Liu Jin Zhao Bing Chang Yan Qi Weihua Liang Feng Li 《Cancer immunology, immunotherapy : CII》2012,61(11):2135-2141
Multiple determinant factors are involved in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Human papillomavirus (HPV) and human leukocyte antigen (HLA) polymorphism were identified as important factors. This study examined the associations between the development of Kazakh ESCC and the determinant factors including HLA-DRB1*0901, 1501; DQB1*0301, 0602; high-risk HPV infection in the area of Xinjiang, China. 200 Kazakh patients with ESCC and 150 controls were recruited, and polymerase chain reaction (PCR) was performed to detect HLA-DRB1*0901, 1501 and DQB1*0301,0602 using sequence-specific primers (SSPs). HPV16 was detected in esophageal specimens using PCR. HPV16 infection rate in Kazakh ESCC case group was 41 %, significantly higher than that of control group 14 % (OR = 3.62; 95 % CI, 2.15–6.09; P < 0.001). A positive association between ESCC and HLA-DRB1*1501 (OR = 2.46, P < 0.0125) or HLA-DQB1*0301 (OR = 3.34, P < 0.0125) alleles was observed. Similar tendencies were observed for HLA-DRB1*1501 (OR = 3.095, P < 0.0125) and HLA-DQB1*0301 (OR = 2.410, P < 0.0125) alleles with HPV16-positive ESCC. HLA-DRB1*1501, HLA-DQB1*0301 and DQB1*0602 were significantly associated with ESCC when the age was ≥55 years (P < 0.0125 for all), whereas only HLA-DQB1*0301 was significantly associated with ESCC when the age was <55 years (P < 0.0125). HLA-DRB1*1501 and HLA-DQB1*0301 were significantly associated with an increase in ESCC occurrence in females (P < 0.0125), whereas only HLA-DQB1*0301 was significantly associated with ESCC in males. Moreover, the occurrence of HLA-DQB1*0602 gene in poorly differentiated ESCC group (68.8 %) was slightly higher than that of well-differentiated squamous cell carcinoma group (31.2 %). The difference was not statistically significant (P > 0.0125). The study suggests that HLA-DRB1*1501 and HLA-DQB1*0301 may influence the immune response to specific tumor and HPV-encoded epitopes and affect the risk of Kazakh ESCC in XinJiang, China. 相似文献
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Dandan Li Weiyan Peng Bin Wu Huan Liu Ruizhen Zhang Ruiqin Zhou Lijun Yao Lin Ye 《Molecules and cells》2021,44(4):267
Metallothionein (MT1M) belongs to a family of cysteine-rich cytosolic protein and has been reported to be a tumor suppressor gene in multiple cancers. However, its role in esophageal carcinoma carcinogenesis remains unclear. In this study, MT1M expression was correlated with tumor type, stage, drinking and smoking history, as well as patient survival. We also studied the regulation and biological function of MT1M in esophageal squamous cell carcinoma (ESCC). We have found that MT1M is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues. Furthermore, restoration of expression by treatment with the demethylation agent A + T showed that MT1M downregulation might be closely related to hypermethylation in its promoter region. Over-expression of MT1M in ESCC cells significantly altered cell morphology, induced apoptosis, and reduced colony formation, cell viability, migration and epithelial-mesenchymal transition. Moreover, based on reactive oxygen species (ROS) levels, a superoxide dismutase 1 (SOD1) activity assay and protein analysis, we verified that the tumor-suppressive function of MT1M was at least partially caused by its upregulation of ROS levels, downregulation of SOD1 activity and phosphorylation of the SOD1 downstream pathway PI3K/AKT. In conclusion, our results demonstrated that MT1M was a novel tumor-suppressor in ESCC and may be disrupted by promoter CpG methylation during esophageal carcinogenesis. 相似文献
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Luis Filipe Costa‐Machado Roberto Martín‐Hernández Miguel Ángel Sanchez‐Luengo Katharina Hess Claudia Vales‐Villamarin Marta Barradas Cian Lynch Daniel de la Nava Alberto Diaz‐Ruiz Rafael de Cabo Marta Cañamero Lola Martinez Marta Sanchez‐Carbayo Daniel Herranz Manuel Serrano Pablo J Fernandez‐Marcos 《EMBO reports》2018,19(9)
The NAD+‐dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non‐small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K‐RAS. Therefore, we investigated the effect of SIRT1 on K‐RAS‐driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K‐RAS in a MEK and PI3K‐dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K‐RasG12V‐driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1‐Tg pneumocytes, isolated shortly after K‐RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K‐RAS‐driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1–K‐RAS axis could be a therapeutic target for NSCLCs. 相似文献
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Yu Han Xiao-He Guo Qing-Fen Zheng Yan-Li Zhu Ying-Ying Fan Xiu-Ying Zhang 《Molecular biology reports》2013,40(3):2473-2483
Substantial evidence has demonstrated that platelet-derived growth factor-D (PDGF-D) is tightly associated with the development and progression of tumors. However, its biological functions in esophageal squamous cell carcinoma (ESCC) remain to be delineated. In this study, we found that expressions of PDGF-D mRNA and protein in ESCC tissues and cells were significantly higher than that in normal esophageal epithelial tissues (P < 0.05), further investigation showed that PDGF-D protein level in EC1 cells was obviously higher than those in EC9706 and Eca109 cells (P < 0.05). Elevated PDGF-D level was closely associated with TNM staging, tumor differentiation and lymph node metastasis (P < 0.05), but not related to the patients’ age and gender (P > 0.05). In addition, down-regulation of PDGF-D expression markedly inhibited proliferation, reduced invasion and induced apoptosis in EC1 cells. More importantly, reduced PDGF-D level evoked the down-regulation of p65 and p-IκBα proteins and elevation of IκBα protein of NF-κB pathway, accompanied with the decreases of bcl-2 and MMP-9 protein expressions and increases of bax protein level and caspase-3 activities. Correctively, our data suggest that PDGF-D plays pivotal roles in the development and progression of ESCC, and combinations with PDGF-D and NF-κB pathway may be effective and feasible molecular targets for therapy of ESCC. 相似文献
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Xiang T Li L Yin X Yuan C Tan C Su X Xiong L Putti TC Oberst M Kelly K Ren G Tao Q 《PloS one》2012,7(1):e29783
Background
Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear.Methodology/Principal Findings
We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells.Conclusions/Significance
UCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer. 相似文献11.
Bo Wang Lian Li Yuan Liao Jinqing Li Xingjuan Yu Yi Zhang Jing Xu Huilan Rao Shupeng Chen Lanjun Zhang Limin Zheng 《Cancer immunology, immunotherapy : CII》2013,62(10):1575-1585
The proinflammatory cytokine interleukin 17 (IL-17) is considered to play a crucial role in diverse human tumors; however, its role in disease progression remains controversial. This study investigated the cellular source and distribution of IL-17 in esophageal squamous cell carcinoma (ESCC) in situ and determined its prognostic value. Immunohistochemistry, immunofluorescence and immunoelectron microscopy were used to identify IL-17-expressing cells in ESCC tissues, paying particular attention to their anatomic localization. Kaplan–Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival in 215 ESCC patients with long-term follow-up (>10 years). The results showed that mast cells, but not T cells or macrophages, were the predominant cell type expressing IL-17 in ESCC tissues. Unexpectedly, these IL-17+ cells were highly enriched in the muscularis propria rather than the corresponding tumor nest (p < 0.0001). The density of IL-17+ cells in muscularis propria was inversely associated with tumor invasion (p = 0.016) and served as an independent predictor of favorable survival (p = 0.007). Moreover, the levels of IL-17+ cells in muscularis propria were positively associated with the density of effector CD8+ T cells and activated macrophages in the same area (both p < 0.0001). This finding suggested that mast cells may play a significant role in tumor immunity by releasing IL-17 at a previously unappreciated location, the muscularis propria, in ESCC tissues, which could serve as a potential prognostic marker and a novel therapeutic target for ESCC. 相似文献
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Paulo Thiago de Souza-Santos Sheila Coelho Soares Lima Pedro Nicolau-Neto Mariana Boroni Nathalia Meireles Da Costa Lilian Brewer Albert Nobre Menezes Carolina Furtado Miguel Angelo Martins Moreira Hector N. Seuanez Tatiana de Almeida Simão Luis Felipe Ribeiro Pinto 《Translational oncology》2018,11(6):1283-1291
Esophageal squamous cell carcinoma (ESCC) is a frequent and lethal neoplasia. As recent advances in targeted therapy have not improved ESCC prognosis, characterization of molecular alterations associated to this tumor is of foremost relevance. In this study, we analyze, for the first time, the complete genomic profile of ESCC by RNA-seq. TP53 was the most frequently mutated gene in the investigation and validation sets (78.6% and 67.4%, respectively). Differential expression analysis between tumor and nontumor adjacent mucosa showed 6698 differentially expressed genes, most of which were overexpressed (74%). Enrichment analysis identified overrepresentation of Wnt pathway, with overexpressed activators and underexpressed inactivators, suggesting activation of canonical and noncanonical Wnt signaling pathways. Higher WNT7B expression was associated with poor prognosis. Twenty-one gene fusions were identified in 50% of tumors, none of which involving the same genes in different patients; 71% of fusions involved syntenic genes. Comparisons with TCGA data showed co-amplification of seven gene pairs involved in fusions in the present study (~33%), suggesting that these rearrangements might have been driven by chromoanagenesis. In conclusion, genomic alterations in ESCC are highly heterogeneous, impacting negatively in target therapy development. 相似文献
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Li Mai Faping Yi Xiaoyan Gou Ji Zhang Changdong Wang Geli Liu Youquan Bu Chengfu Yuan Linman Deng Fangzhou Song 《Molecular and cellular biochemistry》2014,392(1-2):95-107
MCPH1, initially identified as an hTERT repressor, has recently been implicated in mediating DNA damage response and maintaining chromosome integrity. This study is to investigate its potential role in the onset of cervical cancer. In the study, decreased expression of MCPH1 was observed in 19 of 31 cases (61.3 %) at mRNA level and 44 of 63 cases (69.8 %) at protein level of cervical tumor tissues compared with the paired nontumor tissues. Reduced MCPH1 protein expression was significantly associated with high-tumor grade (1 vs. 3 P = 0.013; 2 vs. 3 P = 0.047). In addition to inhibit SiHa cell migration and invasion, the overexpression of MCPH1 inhibited cervical cancer cells growth through inducing S phase arrest and mitochondrial apoptosis. Further analysis demonstrated cyclinA2/CDK2, CDC25C-cyclinB/CDC2, and p53/p21 pathways were involved in the MCPH1 overexpression-induced S phase arrest. Moreover, the overexpression of MCPH1 activated mitochondrial apoptosis through regulating several apoptosis-related proteins such as p53, Bcl-2, Bax, cytochrome c, caspase-3, and PARP-1. Our findings indicate that downregulated MCPH1 correlates with tumor progression in cervical cancer, and MCPH1 has an important role in regulating cell growth through regulating the cell cycle and apoptosis. Thus, it may be a crucial tumor suppressor gene and a novel candidate therapeutic target for cervical cancer. 相似文献
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Wen-Qing Li Nan Hu Zhaoming Wang Kai Yu Hua Su Lemin Wang Chaoyu Wang Stephen J. Chanock Laurie Burdett Ti Ding You-Lin Qiao Jin-Hu Fan Yuan Wang Yi Xu Carol Giffen Xiaoqin Xiong Gwen Murphy Margaret A. Tucker Sanford M. Dawsey Neal D. Freedman Christian C. Abnet Alisa M. Goldstein Philip R. Taylor 《PloS one》2013,8(7)
The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10−3). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms. 相似文献
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Chen LJ Sun J Wu HY Zhou SM Tan Y Tan M Shan BE Lu BF Zhang XG 《Cancer immunology, immunotherapy : CII》2011,60(7):1047-1055
A retrospective cohort study including 112 patients suffering from esophageal squamous cell carcinoma (ESCC) was performed
to investigate the expression of B7-H4 in ESCC and determine its association with patient’s clinicopathological parameters
and survival. Expression levels of B7-H4 on tumor cells and densities of tumor infiltrating lymphocytes (TILs) in the surgical
specimens of ESCC tissues were characterized using immunohistochemical assays. Uni- and multivariate analyses were performed
to evaluate the prognostic value of B7-H4 expression levels and densities of TILs in tumor sections. Positive B7-H4 immunostaining
was observed in 107 of 112 (95.5%) of ESCC tissue sections. We further divided all patients into two major subgroups, a lower
B7-H4 expression group with 46 patients and a higher B7-H4 expression group with 66 patients. We found that expression levels
of B7-H4 on tumor cells were significantly correlated with patient’s gender (P = 0.0288), distant metastasis (P = 0.0500), and TNM stage (P = 0.0258). Moreover, tumor cell B7-H4 expression was inversely correlated with densities of CD3+ T cells in tumor nest (P = 0.0424) and CD8+ T cells in tumor stroma (P = 0.0229). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the
patients with lower B7-H4 expression (P = 0.0105, Hazard Ratio: 1.854, 95%CI:1.152–2.902). Markers of cell-mediated immune responses such as CD3, CD8, and T-bet
were associated with better patient survival. The present study demonstrated that B7-H4 expression in human ESCC is associated
with cancer progression, reduced tumor immunosurveillance and worse patient outcomes. B7-H4 can serve as a novel prognostic
predictor for human ESCC and a potential target for the immune therapy against this malignancy. 相似文献
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《Epigenetics》2013,8(10):1366-1373
Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC. 相似文献
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