Zhejiang Province Cancer Hospital

Hangzhou, China

Zhejiang Province Cancer Hospital

Hangzhou, China
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Jiang Y.,CAS Shanghai Institutes for Biological Sciences | Xie X.,CAS Shanghai Institutes for Biological Sciences | Li Z.,CAS Shanghai Institutes for Biological Sciences | Wang Z.,CAS Shanghai Institutes for Biological Sciences | And 4 more authors.
Cancer Research | Year: 2011

Raf kinase trapping to Golgi (RKTG) is a potential tumor suppressor gene due to its negative roles in regulating Ras/Raf/MEK/ERK (extracellular signal-regulated kinase) pathway and GPCR (G protein-coupled receptor) Gbg subunit signaling. Interestingly, RKTG-deficient mice are free of tumors, although they are prone to form skin cancer on carcinogen administration. On the other hand, p53 is a well-characterized tumor suppressor gene and p53 heterozygous mice develop sarcoma and other tumors starting from 12 months of age. In RKTG-null mouse embryonic fibroblasts, lypophosphatidic acid (LPA), but not EGF (epidermal growth factor), could stimulate hyperphosphorylation of AKT and GSK3b, accompanied by increases in phosphorylation of p53 at Ser15 and accumulation of p53, as well as its target genes p21 and p16. Spontaneous skin cancer-like tumors were detected in about 25% of RKTG nullizygous and p53 heterozygous mice within 7 months of age. Hyperplasia and epithelial-mesenchymal transition (EMT) were observed in the tumor-overlying epidermis, in which LOH of p53 occurred and EMT features emerged. In p53-mutated A431 epithelial carcinoma cells, knockdown of RKTG led to enhancement of LPA-stimulated AKT and GSK3b phosphorylation, together with increased accumulation of b-catenin and appearance of EMT features that were antagonized by p53 overexpression. In HepG2 epithelial cells, LPA-stimulated AKT phosphorylation and EMT features reached maximum when both RKTG and p53 were simultaneously silenced. In summary, these results not only indicate that RKTG has an in vivo tumor suppressor function to cooperate with p53 in tumorigenesis but also suggest that p53 has an EMT checkpoint function and the loss of this function can combine with loss of RKTG to drive EMT and tumor progression. © 2011 American Association for Cancer Research.


Yang H.,Fudan University | Liu Y.,Fudan University | Bai F.,University of North Carolina at Chapel Hill | Zhang J.-Y.,Fudan University | And 10 more authors.
Oncogene | Year: 2013

The TET (ten-eleven translocation) family of -ketoglutarate (-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine, leading to eventual DNA demethylation. The TET2 gene is a bona fide tumor suppressor frequently mutated in leukemia, and TET enzyme activity is inhibited in IDH1/2-mutated tumors by the oncometabolite 2-hydroxyglutarate, an antagonist of -KG, linking 5mC oxidation to cancer development. We report here that the levels of 5hmC are dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers when compared with the matched surrounding normal tissues. Associated with the 5hmC decrease is the substantial reduction of the expression of all three TET genes, revealing a possible mechanism for the reduced 5hmC in cancer cells. The decrease of 5hmC was also observed during tumor development in different genetically engineered mouse models. Together, our results identify 5hmC as a biomarker whose decrease is broadly and tightly associated with tumor development. © 2013 Macmillan Publishers Limited All rights reserved.


Ling Z.Q.,Zhejiang Province Cancer Hospital | Guo W.,University of Chinese Academy of Sciences | Lu X.X.,Zhejiang Province Cancer Hospital | Zhu X.,Zhejiang Province Cancer Hospital | And 3 more authors.
Annals of Oncology | Year: 2014

Background: The aim of this study is to determine whether PAQR3, a protein specifically localized in the Golgi apparatus, is associated with tumor progression, metastasis and survival of human patients with gastric cancer. Patients and methods: PAQR3 expression status was investigated in a large panel of gastric cancer (n = 300) and their corresponding para-cancerous histological normal tissues (PCHNT) at both mRNA and protein levels. The correlation of PAQR3 expression levels with clinical features such as metastasis and prognosis was analyzed. The effect of PAQR3 on the growth and migration of gastric cancer cells was also determined. Results: PAQR3 was frequently down-regulated in gastric cancer samples compared with PCHNT at both mRNA and protein levels (both P < 0.0001). The expression level of PAQR3 was negatively correlated with Helicobacter pylori infection (P < 0.0001), tumor size (P < 0.0001), tumor stage (P < 0.0001), venous and lymphatic invasion (P < 0.0001), distant and nodal metastasis (P < 0.0001), and patient survival (P < 0.0001). Down-regulation of PAQR3 was highly correlated with increased epithelial-mesenchymal transition (EMT) in gastric cancer samples. In addition, PAQR3 overexpression was able to negatively modulate cell proliferation, migration and EMT of gastric cancer cells. Conclusion: PAQR3 is markedly down-regulated in human gastric cancers. PAQR3 expression level is closely associated with the progression and metastasis of gastric cancers. PAQR3 is also a new genetic signature that can predict the prognosis of the patients with gastric cancer. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Liu X.,Zhejiang Province Cancer Hospital | Ling Z.-Q.,Zhejiang Province Cancer Hospital
Histology and Histopathology | Year: 2015

In recent years, frequent isocitrate dehydrogenase 1/2 (IDH1/IDH2) gene mutations were found in a variety of tumors, which specifically alter arginine residues of catalytic active site in IDH1/IDH2 and confer new enzymatic function of directly catalyzing alpha-ketoglutarate (α-KG) to R-2-hydroxyglutarate (2- HG). 2-HG could competitively inhibit α-KG–dependent enzymes and might therefore contribute to tumorigenesis. In addition, mutation status of IDH1/IDH2 is closely related to the progress and prognosis of certain tumors. Thus IDH1/IDH2 is considered to be a promising biomarker for early diagnosis and prognosis and targeted therapy. In this study, the current research on IDH1/IDH2 mutation, especially the mechanisms and clinical characteristics related to tumor, are reviewed. © 2015, Histology and Histopathology. All rights reserved.


WANG C.C.,Zhejiang Province Cancer Hospital
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery | Year: 2011

To investigate the relationship between methylation status of APC gene in both peripheral blood and tumor tissues and clinical-pathology characteristics in patients with esophageal squamous cell carcinoma(ESCC), and to study the dynamic change of APC methylation in peripheral blood in the perioperative period. Real-time MSP technique was used to detect methylation status of APC in tumor tissues, adjacent normal tissues and peripheral blood on the day before the surgery, intraoperative, postoperative day 7 in 76 cases with ESCC. Sixty healthy volunteers matched by age and gender were randomly selected as controls. The methylation rate of APC in tumor tissue and peripheral blood was 44.74%(34/76) and 42.11%(32/76), respectively, which were significantly higher than that in adjacent normal tissue and controls [6.58%(5/76) and 1.67%(1/60), P=0.000]. The methylation rates showed good agreement between tumor tissues and peripheral blood, which could be verified by ROC curve(A Zeta=0.849, P=0.000). APC methylation rate was significantly related to pathological staging, lymph node metastasis, depth of invasion, and invasion of nerve and vessel (P<0.05). The results demonstrated that family history of cancer was independently associated with APC methylation in peripheral blood(P<0.05). DNA methylation rates in peripheral blood showed an initial increase and then decreased in the preoperative period, intraoperative and postoperative. The methylation rates of APC among free DNA in peripheral blood in patients with ESCC reflect tumor progression, and decrease with the solid tumour resection.


Yuan J.M.,Zhejiang Province Cancer Hospital
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery | Year: 2011

To study the change of lymphocyte subgroups in the peripheral blood of patients with gastric carcinoma and its association with survival. Flow cytometry was used to examine the subgroups of lymphocytes (CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+), CD19(+), CD25(+), CD44(+) and NK cells) in the peripheral blood of 833 gastric carcinoma patients prior to any therapy. Patients were divided into the high expression group and lower expression group according to the average test values of 96 healthy control subjects. Survival rate was compared between the two groups. Compared with control group, the levels of CD3(+) and CD8(+) T cell in patients were significantly lower, while the levels of CD4(+), CD19(+), CD25(+), CD4(+)/CD8(+), CD44(+), and NK(+) cells were significantly. The differences were statistically significant(P<0.05). Three-year survival rates of gastric cancer patients with high CD19(+) expression (n=444) and cases with low CD19(+) expression (n=389) were 36.4% and 18.5%, respectively(P<0.05). The expressions of other seven types of lymphocytes were not associated with survival rates (all P>0.05). Significant changes in lymphocyte subgroups exist in the peripheral blood of patients with gastric carcinoma. Patients with high CD19(+) expression have better survival.


Lu X.-X.,Zhejiang Province Cancer Hospital | Yu J.-L.,Zhejiang Province Cancer Hospital | Ying L.-S.,Zhejiang Province Cancer Hospital | Han J.,Zhejiang Province Cancer Hospital | And 5 more authors.
Cancer | Year: 2012

Background: Helicobacter pylori has been recognized as a definite carcinogen for gastric cancer (GC); however, the pathogenesis of H. pylori infection remains unclear. Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene whose deficiency is causally related to GC. However, in H. pylori infection-associated GC, the role of RUNX3 has not been studied. Methods: The authors used real-time methylation-specific polymerase chain reaction analysis to determine methylation status of the RUNX3 promoter in a spectrum of gastric lesions, including 220 samples of chronic atrophic gastritis, 196 samples of intestinal metaplasia, 134 samples of gastric adenoma, 102 samples of dysplasia, and 202 samples of GC with paired noncancerous mucosa tissues and corresponding blood specimens. The association of abnormal methylation with precancerous gastric lesions was evaluated along with the association between RUNX3 methylation and H. pylori infection, and the concordance of methylation levels was investigated between serum and tissues. Results: The results indicated that increasing RUNX3 promoter methylation was correlated with distinct stages of GC progression. GC tissues had the highest methylation proportion (75.2%) compared with precancerous gastric lesions, including chronic atrophic gastritis (15.9%), intestinal metaplasia (36.7%), gastric adenoma (41.8%), and dysplasia (54.9%). H. pylori infection, a major risk factor for GC, contributed to the inactivation of RUNX3 in gastric epithelial cells through promoter hypermethylation. The levels of RUNX3 methylation in serum were in significant concordance with the methylation levels observed in GC tissues (P =.887). Conclusions: The current findings supported RUNX3 methylation as a risk factors for the carcinogenesis of chronic atrophic gastritis with H. pylori infection and indicated that circulating RUNX3 methylation is a valuable biomarker for the detection of early GC. © 2012 American Cancer Society.


Ge M.-H.,Zhejiang Province Cancer Hospital
Chinese Journal of Oncology | Year: 2012

Objective: To assess the epidermal growth factor receptor (EGFR) status in salivary adenoid cystic carcinoma and explore its role in cancer invasion. Methods: Fifty-four patients with pathologically confirmed salivary adenoid cystic carcinoma (SACC) were divided into invasion group and non-invasion group. The EGFR expression was determined by immunohistochemstry (SP staining). The relations between the EGFR expression and the SACC clinical pathological characteristics were analyzed. Results: EGFR were mainly expressed in the cell membrane and cytoplasm in the tissue of SACC. The positive rate of EGFR expression in the tumor tissue was 75.9% (41/54), and EGFR was over-expressed in the cytoplasm. The positive rate of EGFR expression in invasion group was higher than that in the non-invasion group (10.0%, P <0.05). EGFR expression were related with the SACC T stages, histological types, distant metastasis, lymph node metastasis, and nerve invasion (P < 0.05). Conclusions: A higher expression of EGFR gene in the cytoplasm may have important effect on the progression of invasive carcinoma. Further investigations are required to develop new strategy in the treatment of salivary adenoid cystic carcinoma.


Wu Y.-C.,Zhejiang Province Cancer Hospital | Ling Z.-Q.,Zhejiang Province Cancer Hospital
Histology and Histopathology | Year: 2014

Tumorigenesis correlates with hypermethylation of tumor suppressors and hypomethylation of oncogenes. DNA methyltransferases (DNMTs) catalyze DNA methylation, and mutations and aberrant expression in DNMT genes are found in multiple human tumors. The discovery of the DNA demethylation function of TET proteins has opened up new avenues for the study of DNA methylation regulation. TET proteins regulate the DNA demethylation pathway through oxidizing 5-mC into 5-hmC, 5-fC, and 5-aC. TET genes have been reported to be frequently mutated in hematopoietic malignancies and are associated with the malignant transformation of cells. Loss-of-function mutations in TET genes have not been reported in human solid tumors. However, 5-hmC has been found to be reduced in various solid tumors, indicating that TET genes may contribute to cellular transformation via regulation of DNA demethylation. As a new epigenetic modification, 5-hmC may be a useful biomarker for the diagnosis of cancers. To better understand the roles of TET and 5-hmC in tumors, the biological functions of TET and 5-hmC should be studied further.


Ling Z.Q.,Zhejiang Province Cancer Hospital | Zhao Q.,Zhejiang Province Cancer Hospital | Zhou S.L.,Zhejiang Province Cancer Hospital | Mao W.M.,Zhejiang Province Cancer Hospital
European Journal of Surgical Oncology | Year: 2012

Background: Tumor-specific alterations of DNA methylation in circulating DNA have been associated with tumor burden and malignant progression. A wealth of information indicating the potential use of DNA methylation in circulating DNA for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this study, we examined prospectively whether the presence of plasma DNA with tumor characteristics before oesophagectomy is a predictive factor related to disease-free survival (DFS). Methods: Promoter hypermethylation of MSH2 was analyzed using real-time methylation-specific PCR (real-time MSP) in paired tumor and plasma samples of 209 patients with esophageal squamous cell carcinoma (ESCC). Results: Aberrant MSH2 methylation was found in 101 of 209 ESCC patients. Of these 101 patients, 77 cases exhibited the same alteration in their plasma DNA. No alterations were found in the plasma DNA of the remaining 108 patients. As a control, we screened for aberrant methylation in the plasma DNA of 60 health individuals. No methylation was found in plasma DNA of these control groups. Follow-up analysis indicated significantly lower DFS for patients with high MSH2 methylation compared to those with MSH2 unmethylation after surgery. Conclusions: It was suggestted that MSH2 methylation in the plasma would be a good predictor of DFS for these ESCC patients before oesophagectomy. © 2011 Elsevier Ltd. All rights reserved.

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