Lianhai Zhang

Peking University Cancer Hospital, Peping, Beijing, China

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Publications (15)28.25 Total impact

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    ABSTRACT: Although preclinical work with rapalogs suggests potential in the treatment of gastric cancer, they have been less successful clinically. In this study, we report the impact of the investigational drug PP242, a potent and selective small-molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis. The antiproliferative effect of PP242 was assessed using the Cell Counting Kit-8 assay. The migration and invasion potential were analyzed using wound-healing and transwell assays, respectively. The Matrigel capillary tube formation assay was performed to mimic in-vivo angiogenesis. Immunoblotting and immunofluorescence were used to observe protein levels and distribution of actin fibers. Finally, p-mammalian target of rapamycin (mTOR) expression was detected on gastric cancer tissues using immunohistochemistry. First, PP242 potently inhibited cell proliferation in gastric cancer cell lines and in human endothelial cells in vitro at the IC50 ranged from 50 to 500 nmol/l. Then, an inhibitory effect of PP242 on metastasis was observed in gastric cancer cell AGS, along with the cytoskeletal rearrangements and suppression of the phosphorylation of PI3K downstream factors including AKT, mTOR, and P70S6K. Furthermore, PP242 was found to decrease the tube formation and migration of human umbilical vein endothelial cells. Using immunohistochemistry, we found that p-mTOR staining was observed in 41.8% (82/196) of gastric cancer tissues and correlated with depth of mural invasion, lymph node metastasis, tumor node metastasis stage, and vascular invasion. These results show that PP242 suppresses cell proliferation and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway, which might be an effective novel therapeutic candidate against gastric cancer in the future.
    Anti-cancer drugs. 07/2014;
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    ABSTRACT: Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5-year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole-genome analysis of 131 Chinese gastric cancer tissue specimens using whole-genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1-amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 06/2014; · 3.55 Impact Factor
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    ABSTRACT: To clarify the relationship between clinicopathological features and lymph node metastasis and to propose the potential indications of lymph node metastasis for prognosis in early gastric cancer (EGC) patients. We retrospectively observed 226 EGC patients with lymph node resection, and analyzed the associations between lymph node metastasis and clinicopathological parameters using the chi-square test in univariate analysis and logistic regression analysis in multivariate analysis. Overall survival analysis was determined using the Kaplan-Meier and log-rank test. We conducted multivariate prognosis analysis using the Cox proportional hazards model. Of all the EGC patients, 7.5% (17/226) were histologically shown to have lymph node metastasis. The differentiation, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in EGC. The 5- and 10-year survival rates were significantly lower in patients with lymph node metastasis than in those without and the patients also had shorter progress-free survival time. Lymph node metastasis and tumor size were independent prognostic factors for EGC. The status of the lymph nodes was a significant factor in predicting recurrence or metastasis after surgery. The undifferentiated carcinoma and lymphovascular and/or submucosal invasion were associated with a higher incidence of lymph node metastasis in EGC patients, whom need to perform subsequent D2 lymphadenectomy or laparoscopic lymph node dissection and more rigorous follow-up or additional chemotherapy/radiation after D2 gastrectomy for poor prognosis and high recurrence/metastasis rate.
    Chinese Journal of Cancer Research 04/2014; 26(2):192-9. · 0.45 Impact Factor
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    ABSTRACT: The programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer. Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study. Circulating PD-L1 expression was tested by enzyme-linked immunosorbent assay (ELISA). The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically. Expression of PD-L1 in advanced gastric cancer patients was significantly up-regulated compared with health people (P=0.006). The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis (P=0.026 and P=0.041, respectively). Although we didn't find significant difference in all advanced gastric cancer patients with different PD-L1 expression, the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients (65.6% vs. 44.7%, P=0.028). PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.
    Chinese Journal of Cancer Research 02/2014; 26(1):104-11. · 0.45 Impact Factor
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    ABSTRACT: To investigate the expression of serum endothelial cell specific molecule 1(ESM-1) in gastric cancer and to evaluate the effect of serum ESM-1 as a potential serum biomarker. Serum ESM-1 was detected by enzyme-linked immunosorbent assay(ELISA) and CEA, CA19.9, CA72.4 were detected by electrochemiluminescence immunoassay(ECLIA) in 102 patients with gastric cancer preoperatively. At the same time, serum ESM-1, CEA, CA19-9, CA72-4 in 41 healthy adults volunteers were detected with the same method. In addition, the follow-up data of all the patients were collected. Compared to healthy volunteers, the serum ESM-1 level in gastric cancer patients increased(P<0.01). The sensitivity and specificity of serum ESM-1 were 73.9% and 51.2% respectively. In contrast, the sensitivities of CEA, CA19-9 and CA72-4 were only 16.1%, 18.3% and 23.2% respectively. High level of serum ESM-1 indicated poor outcomes(P<0.05). Serum ESM-1 increases in the peripheral blood of the gastric cancer patients. It may be a potential serum marker to help diagnosis and prediction of prognosis of gastric cancer patients.
    Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 01/2014; 17(1):51-5.
  • Lin Li, Lianhai Zhang, Jiafu Ji
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    ABSTRACT: Considerable concentrations of circulating nucleic acids have been reported in peripheral blood from cancer patients. These circulating nucleic acids bear a variety of tumor-specific information and potentially represent a stable source of non-invasive tumor biomarkers. The assessable genetic and epigenetic changes of circulating nucleic acids include DNA mutations, copy number alterations, abnormal methylation and disruption of microRNA. Such alterations reflecting molecular characteristics of tumor tissues, provide a new clue for noninvasive, real-time and monitoring test. In the present article, the main findings of research status related to the utility of circulating nucleic acids for early diagnosis, prognosis and monitoring of gastric cancer are reviewed. In addition, the advantage, the examination technique and the application prospection of circulating nucleic acids as tumor markers are also reviewed.
    Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 01/2014; 17(1):21-5.
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    ABSTRACT: PRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants. PRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro. Positive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P < 0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P = 0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(DeltaCAAX) mutants accompanied with its alteration in subcellular localization. Metastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.
    Journal of Translational Medicine 12/2013; 11(1):309. · 3.46 Impact Factor
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    ABSTRACT: CMTM3 (CKLF-like MARVEL transmembrane domain containing 3) is a novel tumor suppressor gene with frequent epigenetic inactivation. In this study, we demonstrated the role played by CMTM3 in gastric cancer cells as a TSG, and examined the correlation between CMTM3 expression and clinicopathological parameters by immunohistochemistry in gastric cancer patients with different pathological stages (n = 350). We found that CMTM3 expression was reduced or silenced by epigenetic regulation in gastric cell lines, and dramatically downregulated in primary gastric cancer tissues. Restoration of CMTM3 significantly affected migration and invasion of AGS and SGC-7901 cells (P < 0.001). In vivo experiments showed that peritoneal disseminated metastases were significantly suppressed by CMTM3 (P < 0.001). We further showed that the expression of MMP2 and the phosphorylation of Erk1/2 were decreased when CMTM3 was restored. In addition, by immuohistychemisty staining, we found that the expression of CMTM3 was remarkably weaker in gastric cancer tissues than that in normal mucosae (P = 0.008), and was significantly correlated with Gender (P = 0.033), Tumor Depth (P = 0.049), Stage (P = 0.021), Histologic Grade (P = 0.022). More importantly, CMTM3 expression was associated with prognosis in gastric cancer patients (P = 0.041), and was a significant independent prognostic indicator (HR = 0.704, 95%CI, 0.498 to 0.994; P = 0.046). Our findings indicate that CMTM3 regulates migration and invasion of gastric cancer cells. Moreover, CMTM3 is a candidate marker for prognosis of gastric cancer in clinic. This article is protected by copyright. All rights reserved.
    Cancer Science 10/2013; · 3.48 Impact Factor
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    Chuang Tian, Lianhai Zhang, Daohu Hu, Jiafu Ji
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    ABSTRACT: This study aims to investigate the roles of ghrelin signaling in human gastric carcinoma cell lines AGS and SGC7901. Effects of ghrelin signaling on CDK6, P53, NF-κB/P65 and MMP2 mRNA and/or protein expression were determined by real-time PCR and western blot. MTT method and flow cytometry were performed to assess the gastric cancer cell proliferation. The SGC7901 cells overexpressing ghrelin were inoculated into nude mice to produce tumors which were measured later. The wound-healing assay and cell invasion assay were used to test the cell migration and invasive ability of gastric cancer. Ghrelin signaling promotes the oncogene CDK6 gene expression and represses the tumor suppressor gene P53 gene expression in gastric cancer. Ghrelin activates NF-κB/P65 signaling pathway through GHS-R in gastric cancer. Ghrelin upregulates the metastasis factor MMP2 expression via GHS-R/NF-κB signaling pathway in gastric cancer cells and promotes tumor cells migration and invasion, suggesting that ghrelin signaling is a critical pathway in cancer metastasis. Ghrelin induces cell proliferation, migration and invasion via GHS-R/NF-κB signaling pathway in gastric cancer cells. Ghrelin treatment must be avoided for gastric cancer patients.
    Molecular and Cellular Biochemistry 06/2013; · 2.33 Impact Factor
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    ABSTRACT: OBJECTIVE: To investigate Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) expressions in gastric cancer and to evaluate its clinical significance. METHODS: LGR5 expression was assessed by immunohistochemistry in 257 gastric cancer patients after surgery. The relationships between LGR5 expression and clinicopathological features and patients prognosis were statistically analyzed. RESULTS: The expression of LGR5 was significantly higher in gastric cancers as a cancer stem cell marker than in adjacent normal tissues (P<0.001), and more frequently in patients with intestinal type, well-moderate differentiation and stage I and II (P<0.05). Although we found gastric cancer patients with LGR5 positive expression had a poorer prognosis, it didn't meet statistical significance (P>0.05). LGR5 negative expression was significantly related to the favorable overall survival in stage I and II gastric cancer patients (P<0.05). Furthermore, patients with high LGR5 expression tended to be more likely to get progression and have poorer progress-free survival (P<0.05). Multivariate Cox regression analysis revealed that LGR5 expression was an independent factor of overall survival for the patients with stage I and II gastric cancer (P<0.05). CONCLUSIONS: Our results show that LGR5 may play an important role in tumorigenesis and progression and would be a powerful marker to predict the prognosis of patients with stage I and II gastric cancer.
    Chinese Journal of Cancer Research 02/2013; 25(1):79-89. · 0.45 Impact Factor
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    ABSTRACT: OBJECTIVE: To analyze the differences in clinicopathologic characteristics and prognosis between mucinous gastric carcinoma (MGC) and signet-ring cell carcinoma (SRCC). METHODS: Clinicopathologic and prognostic data of 1,637 patients with histologically confirmed MGC or SRCC who received surgical operations in the Department of Gastroenterological Surgery, Beijing Cancer Hospital between December 2004 and December 2009 were retrospectively collected and analyzed. The clinicopathological features were analyzed statistically using χ(2) test. Survival was analyzed using the Kaplan-Meier method and multivariate analysis of Cox proportional hazards regression model (backward, stepwise). RESULTS: A total of 181 patients with gastric cancer (74 MGC, 107 SRCC) were included. MGC, when compared with SRCC, was featured by senile patients, stage III and IV, upper third stomach, large tumor size, positive lymph node metastasis, and positive lymphatic vascular invasion (P<0.05). The overall 5-year survival rate showed no difference between the two groups (48.8% vs. 44.8%, P>0.05). However, the survival rate for MGC patients was significant lower than that for SRCC patients when compared among the age <60 years, negative distant metastasis, and tumor localized at upper third stomach (P<0.05). Multivariate Cox proportional hazards models revealed that distant metastasis was a significant independent prognostic indicator in MGC group, and lymph node metastasis and distant metastasis was significant independent prognostic indicators in SRCC group. CONCLUSIONS: While compared with SRCC, MGC is associated with a more aggressive tumor biologic behavior. There is no statistically significant difference in distant metastasis, an independent prognostic indicator for both MGC and SRCC, which might be the reason for no significant difference of the overall survival rate between the patients with MGC and SRCC.
    Chinese Journal of Cancer Research 02/2013; 25(1):32-38. · 0.45 Impact Factor
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    ABSTRACT: The objective of this study was to investigate the independent correlated factors for lymph node metastasis (LNM) and prognosis in T2 gastric cancer patients. A total of 135 pathologically confirmed T2 gastric cancer patients who received a gastrectomy at the Beijing University Cancer Hospital from Dec 1999 to Dec 2006 were studied retrospectively. The potential correlated factors for LNM and patients' prognosis were analyzed, including gender, age, tumor location and size, depth of invasion, lymphatic vascular invasion (LVI), differentiation grade, histological type, Borrmann type, LNM, distant metastasis, TNM stage, and whether the patient was treated with a radical gastrectomy. LNM occurred in 69 patients, which represents a rate of LNM of 51.1 %. Multivariate logistic regression analysis showed that LVI and TNM stage were independent risk factors for LNM (p values were 0.002 and 0.029, respectively). The median follow-up time was 60.3 months. Multivariable survival analysis revealed that age (<60 vs. ≥60), TNM stage and LVI were independent prognostic factors for gastric cancer patients (p values were <0.001, 0.047, and 0.001, respectively). In conclusion, LVI was an independent factor for LNM and the prognosis of resectable T2 gastric cancer patients.
    Tumor Biology 01/2013; · 2.52 Impact Factor
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    ABSTRACT: The purpose of this study is to detect the clinicopathology of gastrointestinal stromal tumors (GISTs) occurring synchronously with gastric adenocarcinomas and to unveil the potential underlying relationship between the synchronous GIST and gastric adenocarcinoma. This study included 15 patients with incidental GISTs found during operations for gastric adenocarcinoma and 30 patients who underwent gastrectomy for gastric cancer without discovering GIST between January 2005 and December 2010 at the Beijing Cancer Institute. We collected the clinicopathological data and analyzed the KIT/PDGFRA mutational status of GISTs, corresponding gastric adenocarcinoma specimens, and the normal tissue around the cancer lesions. Additionally, as a control group, the mutational status of the patients with gastric adenocarcinoma and no other tumors was assayed. Overall, 18 GISTs were found in 15 gastric adenocarcinoma patients. Multiple GIST lesions were found in three cases (20 %). The patients' age ranged from 46 to 85 years, with an average of 67.6 years. The average size of the GISTs was 0.85 cm. All mesenchymal lesions showed low proliferative activity, were of low or very low risk, and were identified as CD117-positive by immunostaining. In GIST lesions, mutations in KIT were detected in 7 out of 13 cases, and of these mutations, 6 were found in exon 11 (46.2 %), and 1 was found in exon 9 (7.7 %). A total of five deletions and one point mutation were in exon 11, and one insertion was in exon 9. Mutations were not detected in exon 17 or 13 of KIT. There was no remarkable mutation analyzed in the gastric adenocarcinoma lesions or normal tissues from either the test or control groups. Clinicopathological profiles and molecular analysis of KIT/PDGFRA showed no obvious relationship between gastric cancer and GISTs in tumor genesis, such as similar oncogene mutations.
    Tumor Biology 01/2013; · 2.52 Impact Factor
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    ABSTRACT: A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.
    Scientific Reports 01/2013; 3:2992. · 5.08 Impact Factor
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    ABSTRACT: Genomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level. We analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12-20q13.1 (12/72), 20q13.1-20q13.2 (11/72) and 20q13.2-20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis. This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets.
    PLoS ONE 01/2012; 7(4):e29824. · 3.53 Impact Factor