Haili Qian

Publications of Haili Qian

• Antitumor activity of Chidamide in hepatocellular carcinoma cell lines.

  Authors: Haijuan Wang, Yi Guo, Ming Fu, Xiao Liang, Xueyan Zhang, Renzhi Wang, Chen Lin, Haili Qian

  Molecular medicine reports. 04/2012;

  Chidamide, the structural analog of MS-275, is a novel and promising histone deacetylase (HDAC) inhibitor for use in cancer therapy. To investigate its effects on cancer cell growth, MTT assay wasChidamide, the structural analog of MS-275, is a novel and promising histone deacetylase (HDAC) inhibitor for use in cancer therapy. To investigate its effects on cancer cell growth, MTT assay was performed in 10 human cancer cell lines. The data showed that the IC50 of Chidamide ranged from 1 to 13 µM, which was comparable to that of MS-275 in half of the tested cell lines. Furthermore, the growth curve indicated that cell growth was gradually inhibited with an increase in Chidamide dosage, and the inhibition was reversed after drug removal in two hepatocelluclar carcinoma cell lines, BEL-7402 and HCC-9204. To determine cell cycle and apoptosis, FACS was carried out in the BEL-7402 and HCC-9204 cells treated with Chidamide. A decrease in the cell population at S phase and an increase in the cell population at G1 phase occurred in a dose-dependent manner. In addition, Chidamide induced apoptosis and up-regulated p21 mRNA expression. These results suggest that Chidamide may arrest the cell cycle and inhibit the growth of hepatocellular carcinoma cells through up-regulation of p21. Further studies are required to clarify the antitumor activity of Chidamide in vivo and its mechanism in anticancer therapy.

• Aurora-A as an independent molecular prognostic marker in gastric cancer.

  Authors: Jing Wang, Sheng Yang, Haizeng Zhang, Yan Song, Xun Zhang, Haili Qian, Xiaohong Han, Yuankai Shi

  Oncology reports. 07/2011; 26(1):23-32.

  Aurora-A, encoding serine/threonine kinases with a key role in mitosis has been demonstrated to be involved in tumor progression. Hematogenous and lymphatic metastasis are also involved in cancerAurora-A, encoding serine/threonine kinases with a key role in mitosis has been demonstrated to be involved in tumor progression. Hematogenous and lymphatic metastasis are also involved in cancer progression. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) have been implicated in tumor-related angiogenesis and lymphagenesis. The purpose of this study was to analyze the expression and prognostic significance of Aurora-A, VEGFs and VEGFRs in gastric cancer. The expression profiles of Aurora-A, VEGF-A and VEGF-D in gastric cancer cell lines were detected employing real-time reverse transcription polymerase chain reaction and Western blot analysis. The expression levels of Aurora-A, VEGF-A/VEGFR-2, VEGF-D/VEGFR-3 and clinicopathological characteristics were analyzed in 89 gastric cancer patients treated with curative surgery. Univariate analysis demonstrated that histological grade (P=0.052), TNM stage (P<0.001), lymphovascular involvement (P<0.001), Aurora-A (P<0.001) and VEGF-D (P=0.048) were prognostic factors. The presence of Aurora-A was correlated with tumor progression (P=0.053) and shorter survival (P=0.001). Cox multivariate regression analysis demonstrated that Aurora-A positive expression, stage III-IV and lymphovascular involvement were independent unfavorable prognostic factors in gastric cancer. Aurora-A positive expression was predictive for worse outcome in patients without lymph node metastasis (P<0.05) and in patients with stage III-IV (P<0.001). Aurora-A could serve as an independent prognostic marker in gastric cancer and could identify patients with worse outcome even in a relatively early and local disease, thus offering valuable information for administering individualized treatment and/or surveillance for these patients.

• BH3-based Fusion Artificial Peptide Induces Apoptosis and Targets Human Colon Cancer.

  Authors: Yongjun Liu, Yunfeng Li, Haijuan Wang, Jing Yu, Hongwei Lin, Dongkui Xu, Yang Wang, Ailing Liang, Xiao Liang, Xueyan Zhang, Ming Fu, Haili Qian, Chen Lin

  Molecular therapy : the journal of the American Society of Gene Therapy. 05/2009;

  Dysregulation of apoptosis is a pilot event before cancer development and plays important roles for cancer to develop resistance to chemical therapeutics. So exploring strategies to recovery theDysregulation of apoptosis is a pilot event before cancer development and plays important roles for cancer to develop resistance to chemical therapeutics. So exploring strategies to recovery the apoptosis balance is a charming and long-endeavored aim in the attempts to conquer cancers. The present study shows an exciting potency of a fusion peptide to inhibit and target to cancer cells, which is composed of BH3 (Bcl-2 Homology 3) effector domain from PUMA (p53 upregulated modulator of apoptosis) and targeting domain of trans-activator of transcription (TAT) and DV3. The in vitro results demonstrated cancer growth inhibition by the fusion peptide in colon cancer cells, as well as in lung adenocarcinoma cell line and breast carcinoma cell line of human origin. But the viability of HEK293, a noncancerous cell line, was not affected, indicating the cancer specificity of the fusion peptide. Apoptosis activation was induced by the peptide through the mitochondria pathway. In vivo studies displayed its tumor inhibiting ability by intratumoral injection. When the fusion peptide was administered systematically by tail vein, the peptide targeted the established tumors in nude mice. No other organs were significantly involved. The fusion peptide is an artificially designed molecule worthy of further evaluation and development.Molecular Therapy (2009); doi:10.1038/mt.2009.43.

• Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell.

  Authors: Yunfeng Li, Haili Qian, Xiao Li, Haijuan Wang, Jing Yu, Yongjun Liu, Xueyan Zhang, Xiao Liang, Ming Fu, Qimin Zhan, Chen Lin

  The journal of gene medicine. 11/2008;

  BACKGROUND: The extremely poor prognosis of patients with pancreatic ductal adenocarcinoma indicates the need for novel therapeutic approaches. The growth arrest and DNA damage-inducible (Gadd) geneBACKGROUND: The extremely poor prognosis of patients with pancreatic ductal adenocarcinoma indicates the need for novel therapeutic approaches. The growth arrest and DNA damage-inducible (Gadd) gene Gadd45a is a member of a group of genes that are induced by DNA damaging agents and growth arrest signals. METHODS: We evaluated the biological activity of Gadd45a in pancreatic ductal adenocarcinoma cancer-derived cell lines and assessed the efficacy of a combined treatment with adenoviral-mediated expression of Gadd45a (Ad-G45a) and anticancer drug (Etoposide, cisplatin, 5-fluorouracil, respectively) for the PANC1 cell line. RESULTS: Gadd45a is variously expressed in cell lines derived from pancreatic ductal adenocarcinoma cancer and adenoviral-mediated expression of Gadd45a (Ad-G45a) in these cells results in apoptosis via caspase activation and cell-cycle arrest in the G2/M phase. Gadd45a significantly increased the chemosensitivity of PANC1, which may be due to abundant apoptosis induction and cell cycle arrest. By combinational treatment of Ad-G45a infection and chemotherapeutics, Gadd45a expression was elevated to a higher extent in cancer cells with wild-type p53 than in that with knocked-out p53 status, indicating a higher chemosensitivity to cancer chemotherapy. CONCLUSIONS: Gadd45a may be a promising candidate for use in cancer gene therapy in combination with chemotherapeutic agents. Copyright (c) 2008 John Wiley & Sons, Ltd.

• Effect of Ad-TIMP3 on biologic behavior of choriocarcinoma cells in vitro.

  Authors: Yan Chen, Haili Qian, Ying Zhang, Yan Ma, Chen Lin, Yang Xiang

  The Journal of reproductive medicine. 09/2008; 53(8):608-14.

  OBJECTIVE: To investigate the effect of adenovirus delivered tissue inhibitor of metalloproteinases-3 (Ad-TIMP3) on the biologic behavior of choriocarcinoma cells in vitro and to evaluate itsOBJECTIVE: To investigate the effect of adenovirus delivered tissue inhibitor of metalloproteinases-3 (Ad-TIMP3) on the biologic behavior of choriocarcinoma cells in vitro and to evaluate its potential application in choriocarcinoma gene therapy. STUDY DESIGN: An adenovirus expressing TIMP3 (Ad-TIMP3) was transferred into choriocarcinoma cells jeg-3 and bewo. The mRNA and protein expression of TIMP3 were detected by reverse transcriptase polymerase chain reaction and Western blotting. MTT assays performed to study the growth inhibitory and proapoptotic effects of TIMP3 in vitro were examined by FACS and DAPI staining. The effect of Ad-TIMP3 on the abilities of adhesion and invasion were evaluated by adhesion and invasion assay, respectively. RESULTS: TIMP3 was expressed less in jeg-3 and bewo than in HEK293 cells. TIMP3 was up-regulated in both cells as a response to Ad-TIMP3 treatment. Ad-TIMP3 significantly inhibited the growth of jeg-3 and bewo cells by inducing the apoptosis of jeg-3 and bewo. The abilities of adhesion and invasion were inhibited significantly by Ad-TIMP3 as well. Furthermore, TIMP3 exerted a cytotoxic bystander effect on adjacent uninfected cells. CONCLUSION: In addition to its role in inhibiting tumor adhesion and invasion, TIMP3 induced the apoptosis and inhibited the growth of jeg-3 and bewo choriocarcinoma cells. Furthermore, TIMP3 exerted a cytotoxic bystander effect on adjacent uninfected cells. Ad-TIMP3 may be potentially useful in treating choriocarcinoma.

• Ad-PUMA sensitizes drug-resistant choriocarcinoma cells to chemotherapeutic agents.

  Authors: Yan Chen, Haili Qian, Haijuan Wang, Xueyan Zhang, Ming Fu, Xiao Liang, Yan Ma, Qimin Zhan, Chen Lin, Yang Xiang

  Gynecologic oncology. 01/2008; 107(3):505-12.

  PURPOSE/OBJECTIVE: To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents. METHODS: AnPURPOSE/OBJECTIVE: To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents. METHODS: An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents (5-FU, vp16, MTX), was used to treat drug-resistant choriocarcinoma cells jeg-3/vp16 and parental jeg-3. The growth inhibitory and proapoptotic effects of Ad-PUMA both in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated by an analysis of caspase 3 activation and the change of mitochondrial membrane potential. The levels of PUMA, p53 and caspase 3 were detected by Western blotting. RESULT: PUMA was expressed lower in jeg-3/vp16 than in jeg-3. jeg-3/vp16 responded much less sensitively to 5-FU and vp16 treatment than jeg-3, though PUMA was up-regulated in both cells. Exogenous PUMA expression resulted in potent growth suppression of jeg-3/vp16 and jeg-3 through induction of apoptosis. Ad-PUMA sensitized jeg-3 and jeg-3/vp16 to chemotherapeutic agents. When Ad-PUMA 10MOI and 5-FU, vp16 or MTX were combined respectively, IC50 of drugs decreased by 8.66-, 18.66- and 13.06-fold compared with those treated by anticancer drugs alone in jeg-3/vp16, while in jeg-3, IC50 decreased only by 1.80-, 1.78- and 2.76-fold. Ad-PUMA restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents by enhancing apoptosis induced by anticancer drugs. Similar results could be observed in vivo. Xenograft tumors were inhibited by Ad-PUMA or vp16. In the drug-resistant group, the inhibitory rate increased from 14.57% to 78.93% in vp16 and vp16 combined with Ad-PUMA subgroups. While in the parental group, the inhibitory rate increased but slightly, from 66.39% to 71.56%. CONCLUSION: PUMA is an important player in the therapeutic responses to chemotherapeutic agents of choriocarcinoma cells. In addition to its role in inhibiting tumor growth, low dose of Ad-PUMA significantly restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents in vitro and in vivo. Exogenous PUMA is potentially useful as a sensitizer in treating drug-resistant choriocarcinoma.

• Adenovirus carrying TIMP-3: a potential tool for cervical cancer treatment.

  Authors: Ying Zhang, Haili Qian, Chen Lin, Jinghe Lang, Yang Xiang, Ming Fu, Xueyan Zhang, Xiao Liang

  Gynecologic oncology. 01/2008; 108(1):234-40.

  OBJECTIVE: Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit allOBJECTIVE: Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit all of MMPs, and its overexpression can retard many kinds of tumor growth. Especially, a potent bystander effect would make it to be more advisable for treating cervical cancer whose primary growth pattern is to invade adjacent structures. These characters prompted the authors to explore its further applicability in human cervical cancer. METHODS: We constructed a replication deficient adenoviral vector carrying TIMP-3 (Ad-TIMP-3). It was transferred into different cervical cancer cell lines in vitro and was injected into the tumor xenografts of nude mice in vivo. RESULTS: Overexpression of TIMP-3 by adenovirus vector arrested cervical cancer cells in G2/M phase. It also promoted growth inhibition of cancer cells by bystander effects. Ad-TIMP-3 infection produced a more potent cell killing effect than Ad-p53 (P<0.05). A synergic effect was observed when Ad-TIMP-3 and cisplatin (cDDP) were used in combination (D<1). In vivo, Ad-TIMP-3 could inhibit cervical cancer xenografts growth. Compared with Ad-TIMP-3 and cDDP groups, tumor growth in Ad-TIMP-3 combined with cDDP group was inhibited more significantly (P<0.05). CONCLUSION: These findings indicated that Ad-TIMP-3 bear a therapeutic potential for cervical cancer.

• RNA interference of metastasis-associated gene 1 inhibits metastasis of B16F10 melanoma cells in a C57BL/6 mouse model.

  Authors: Haili Qian, Jing Yu, Yunfeng Li, Haijuan Wang, Chongwen Song, Xueyan Zhang, Xiao Liang, Ming Fu, Chen Lin

  Biology of the cell / under the auspices of the European Cell Biology Organization. 11/2007; 99(10):573-81.

  BACKGROUND INFORMATION: MTA1 (metastasis-associated gene 1) has been reported to be overexpressed in cancers with high potential to metastasize. Studies of the molecular mechanisms revealed that MTA1BACKGROUND INFORMATION: MTA1 (metastasis-associated gene 1) has been reported to be overexpressed in cancers with high potential to metastasize. Studies of the molecular mechanisms revealed that MTA1 plays an important role in the process of metastasis of many types of cancer. However, the role of MTA1 in melanoma development is unclear. RESULTS: We have investigated the therapeutic value of MTA1 in the B16F10 melanoma cell line with the C57BL/6 mouse model. Studies in vitro showed that MTA1 promoted the metastatic ability of B16F10 cancer cells. MTA1 down-regulation by RNA interference greatly reversed the malignant phenotypes of cancer cells. Immunohistochemical staining of MTA1 in human melanoma samples confirmed the up-regulation of MTA1 in the process of carcinogenesis. Studies in vivo confirmed down-regulation of MTA1 suppressed the growth and experimental metastasis of B16F10 melanoma cells. CONCLUSIONS: MTA1 plays an important role in melanoma development and metastasis. It has a promising potential as a target for in cancer gene therapy or chemotherapy.

• Arsenic trioxide (As2O3) reduces the invasive and metastatic properties of cervical cancer cells in vitro and in vivo.

  Authors: Jing Yu, Haili Qian, Yunfeng Li, Yang Wang, Xueyan Zhang, Xiao Liang, Ming Fu, Chen Lin

  Gynecologic oncology. 09/2007; 106(2):400-6.

  OBJECTIVES: Arsenic trioxide (As(2)O(3)) was found to induce apoptosis in certain types of cancer cells including acute promyelocytic leukemia, and recently in solid tumors. We have previouslyOBJECTIVES: Arsenic trioxide (As(2)O(3)) was found to induce apoptosis in certain types of cancer cells including acute promyelocytic leukemia, and recently in solid tumors. We have previously demonstrated that As(2)O(3) has a therapeutic effect on cervical cancer by apoptosis promotion in vitro and in vivo. Here we further our study on the role of arsenic trioxide in regulating invasive activity of cervical cancer cells in vitro and in vivo. METHODS: The effects of As(2)O(3) on human cervical cancer cell lines (HeLa, SiHa, Caski) adhesion, migration and invasion were observed by means of cell adhesion test, cell migration test and cell invasion test. The effects of As(2)O(3) on p-IkappaB, MMP-2, E-cadherin, caveolin-1 and beta-catenin protein expressions of tumor cells were determined by Western blot. In addition, the effects of As(2)O(3) on NF-kappaB activity of tumor cells were analyzed by immunoblot in whole lysates, cytosol and nucleus, respectively. In animal experiments, cervical cancer cells TC-1 were injected into tail veins of C57BL/6 mice and then the mice were treated by intraperitoneal injection of different doses As(2)O(3). Lung weights and the foci on the surface of lungs were measured. RESULTS: As(2)O(3) inhibited attachment of tumor cells to Fibronectin and Matrigel, reduced cell motility and inhibited tumor invasion potential. As(2)O(3) treatment also resulted in a positive regulation of caveolin-1, upregulation of E-cadherin and decreased activity of beta-catenin, NF-kappaB and NF-kappaB-regulated gene MMP-2. In animal experiments, lung weights in PBS group (0.31+/-0.07 g) were significantly elevated compared with those in As(2)O(3)-treated groups (0.21+/-0.03 g and 0.17+/-0.03 g) also As(2)O(3) reduced number of metastatic lesions of lungs (15.4+/-3.5 vs. 8.3+/-2.0 and 6.3+/-2.3) in a dose-dependent manner. CONCLUSIONS: This study is the first to report the effectiveness of As(2)O(3) as an inhibitor of cervical cancer invasion both in vitro and in vivo, suggesting a potential clinical application of As(2)O(3) in cervical cancer therapies combining apoptosis induction and metastasis inhibition.

• RNA interference against metastasis-associated gene 1 inhibited metastasis of B16F10 melanoma cell in C57BL/6 model.

  Authors: Haili Qian, Jing Yu, Yunfeng Li, Haijuan Wang, Chongwen Song, Xueyan Zhang, Xiao Liang, Ming Fu, Chen Lin

  Biology of the cell / under the auspices of the European Cell Biology Organization. 06/2007;

  Background information. The metastasis-associated gene 1 (MTA1) has been reported to be overexpressed in cancers with high potential to metastasis. Studies on molecular mechanisms revealed thatBackground information. The metastasis-associated gene 1 (MTA1) has been reported to be overexpressed in cancers with high potential to metastasis. Studies on molecular mechanisms revealed that metastasis-associated gene 1 plays an important role in the process of metastasis of many cancer types. But the role of metastasis-associated gene 1 in melanoma development is unclear. Results. Here we investigated the therapeutic value of metastasis-associated gene 1 in B16F10 cell with C57BL-6 model. Biological studies in vitro showed that metastasis-associated gene 1 promoted the metastatic ability of B16F10 cancer cells. metastasis-associated gene 1 down-regulation by RNA interference (RNAi) greatly reversed the malignant phenotypes of cancer cells. Immunohistochemical staining of metastasis-associated gene 1 in human melanoma samples confirmed the up-regulation of metastasis-associated gene 1 in the process of carcinogenesis. In vivo studies confirmed down-regulation of metastasis-associated gene 1 suppressed the growth and experimental metastasis of B16F10 melanoma cells. Conclusions. Metastasis-associated gene 1 play an important role in melanoma development and metastasis. It bears a promising potential in the application targeting metastasis-associated gene 1 in cancer gene therapy or chemotherapy.

• Therapeutic effect of arsenic trioxide (As2O3) on cervical cancer in vitro and in vivo through apoptosis induction.

  Authors: Jing Yu, Haili Qian, Yunfeng Li, Yang Wang, Xueyan Zhang, Xiao Liang, Ming Fu, Chen Lin

  Cancer biology & therapy. 05/2007; 6(4):580-6.

  Arsenic trioxide (As2O3) induces apoptosis in certain types of cancer cells. But the detailed mechanisms of As2O3 efficacy are not completely known. Here we demonstrate that As2O3 has a therapeuticArsenic trioxide (As2O3) induces apoptosis in certain types of cancer cells. But the detailed mechanisms of As2O3 efficacy are not completely known. Here we demonstrate that As2O3 has a therapeutic effect on cervical cancer in vitro and in vivo. We investigated the As2O3-induced apoptosis in various cervical cancer cells. The apoptosis was triggered by mitochondrial pathway and associated with dissociation of Bcl-2 from Bax and VDAC, then the release of cytochrome c from Bax and VDAC channel, resulting in the activation of caspase-9 and caspase-3. The overexpression of Bcl-2 counteracted the As2O3-mediated apoptosis. The As2O3 treatment also resulted in an increased M phase cell cycle distribution by inducing microtubule polymerization. Two independent death-signaling pathways in cervical cancer cells were activated, one dominated by JNK/p38/GADD45 and one by p53 signals. Further investigation involving assessment of As2O3 on tumor cell growth in mice indicated that As203 also inhibited in vivo tumor growth. As2O3 as an inhibitor of cervical cancer proliferation both in vitro and in vivo suggests a potential clinical application in cervical cancer therapies.

• Induction of protective and therapeutic antitumour immunity using a novel tumour-associated antigen-specific DNA vaccine.

  Authors: Wenxin Sun, Haili Qian, Xueyan Zhang, Chunxia Zhou, Xiao Liang, Dongmei Wang, Ming Fu, Wenbo Ma, Shuren Zhang, Chen Lin

  Immunology and cell biology. 11/2006; 84(5):440-7.

  DNA vaccination has become an attractive immunization strategy against cancer. However, a major problem of DNA vaccination is its limited potency to be taken up by the antigen-presenting cells. InDNA vaccination has become an attractive immunization strategy against cancer. However, a major problem of DNA vaccination is its limited potency to be taken up by the antigen-presenting cells. In contrast, loss of immunogenic epitopes of tumour cells has urged the development of vaccines against multiple epitopes. In this study, we developed a novel strategy for the APC to efficiently cross-present a fusion tumour antigen, which contains both MHC class I-restricted and class II-restricted T-cell epitopes from Her-2/neu and p53 in a cognate manner. The N-terminus of the fusion Her-2/neu, p53 protein was linked to the sequence encoding for human secondary lymphoid-tissue chemokine for secretion and chemokinesis, and the C-terminus of the fusion protein was linked to a cell-binding domain of IgG (Fc portion, the cell-binding domain of IgG) for receptor-mediated internalization. Here, we show that the introduction of fused-gene DNA vaccine by gene gun reduced the size of established tumours and prolonged the lifespan of tumour-bearing mice. Results show that this DNA vaccination strategy can broadly enhance the antigen-specific cellular and humoral immune responses. This vaccine is capable of inducing adaptive immunity and may provide a novel, generic design for the development of therapeutic and preventive DNA vaccines.

• Administration of PUMA adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs.

  Authors: Haijuan Wang, Haili Qian, Jian Yu, Xueyan Zhang, Lin Zhang, Ming Fu, Xiao Liang, Qimin Zhan, Chen Lin

  Cancer biology & therapy. 05/2006; 5(4):380-5.

  Esophageal cancer is one of the most lethal human tumors, characterized by relative chemoresistance and poor prognosis. Researchers have been seeking for multimodality to improve its outcome ofEsophageal cancer is one of the most lethal human tumors, characterized by relative chemoresistance and poor prognosis. Researchers have been seeking for multimodality to improve its outcome of therapy. PUMA (p53 upregulated modulator of apoptosis) is a potent proapoptotic molecule that is rapidly induced in cells following DNA damage and is required for p53-induced apoptosis. We evaluated the therapeutic potential of PUMA adenovirus against esophageal cancer cell lines (KYSE-150, KYSE-410, KYSE-510 and YES-2). Infection with Ad-PUMA (PUMA Adenovirus) resulted in the more powerful cytotoxicity in these cell lines compared with Ad-p53. Furthermore, we assessed the efficacy of a combined treatment with Ad-PUMA and anticancer drug (cisplatin, paclitaxel, 5-fluorouracil, respectively) for these cells and found PUMA significantly increased the chemosensitivity of esophageal cancer cells, which may result from more abundant apoptosis induction. Interestingly, Ad-PUMA was found to be more efficient than Ad-p53 in inhibiting cell growth and enhancing the chemosensitivity of esophageal cancer cell lines irrespective of the p53 status. These results suggest that Ad-PUMA is a potent cytotoxic agent and could be a promising alternative in the cancer gene therapy in combination with chemotherapeutic agents.

• Reduced MTA1 expression by RNAi inhibits in vitro invasion and migration of esophageal squamous cell carcinoma cell line.

  Authors: Haili Qian, Ning Lu, Liyan Xue, Xiao Liang, Xueyan Zhang, Ming Fu, Yongqiang Xie, Qimin Zhan, Zhihua Liu, Chen Lin

  Clinical & experimental metastasis. 02/2005; 22(8):653-62.

  To distinguish aggressive esophageal squamous cell carcinoma from indolent disease is the important clinical challenge. Studies have indicated that metastasis-associated gene 1(Mta1) played a role inTo distinguish aggressive esophageal squamous cell carcinoma from indolent disease is the important clinical challenge. Studies have indicated that metastasis-associated gene 1(Mta1) played a role in the process of metastasis of carcinoma. The overexpression of Mta1 gene has been found in a variety of tumors. To identify the detailed roles of MTA1 protein in the carcinogenesis of esophageal squamous cell carcinoma, this study analyzed the pathological specimens on tissue microarray derived from 72 patients using immunohistochemistry. MTA1 expression increased in the nuclear with the development of esophageal squamous cell carcinoma from normal epithelial cell, dysplasia, to invasive cancer. In biological studies with human esophageal squamous cell carcinoma cell line, MTA1 plays its roles to promote cancer cell invasion, adhesion and movement. RNA interference (RNAi) against MTA1 decreased the malignant phenotypes. Gene microarray analysis revealed some metastasis-associated genes were altered by MTA1 RNAi. This study started an effective beginning to explore metastasis mechanisms and cancer gene therapy strategy targeting MTA1.

• Ad-PUMA sensitizes drug-resistant choriocarcinoma cells to chemotherapeutic agents

  Authors: Yan Chen, Haili Qian, Haijuan Wang, Xueyan Zhang, Ming Fu, Xiao Liang, Yan Ma, Qimin Zhan, Chen Lin, Yang Xiang

  Gynecologic Oncology.

  Purpose/Objective.To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents.Methods.An adenovirusPurpose/Objective.To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents.Methods.An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents( 5-FU, vp16, MTX), was used to treat drug-resistant choriocarcinoma cells jeg-3/vp16 and parental jeg-3. The growth inhibitory and proapoptotic effects of Ad-PUMA both in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated by an analysis of caspase 3 activation and the change of mitochondrial membrane potential. The levels of PUMA, p53 and caspase 3 were detected by Western blotting.Result.PUMA was expressed lower in jeg-3/vp16 than in jeg-3. jeg-3/vp16 responded much less sensitively to 5-FU and vp16 treatment than jeg-3, though PUMA was up-regulated in both cells. Exogenous PUMA expression resulted in potent growth suppression of jeg-3/vp16 and jeg-3 through induction of apoptosis. Ad-PUMA sensitized jeg-3 and jeg-3/vp16 to chemotherapeutic agents. When Ad-PUMA 10MOI and 5-FU, vp16 or MTX were combined respectively, IC50 of drugs decreased by 8.66-, 18.66- and 13.06-fold compared with those treated by anticancer drugs alone in jeg-3/vp16, while in jeg-3, IC50 decreased only by 1.80-, 1.78- and 2.76-fold. Ad-PUMA restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents by enhancing apoptosis induced by anticancer drugs. Similar results could be observed in vivo. Xenograft tumors were inhibited by Ad-PUMA or vp16. In the drug-resistant group, the inhibitory rate increased from 14.57% to 78.93% in vp16 and vp16 combined with Ad-PUMA subgroups. While in the parental group, the inhibitory rate increased but slightly, from 66.39% to 71.56%.Conclusion.PUMA is an important player in the therapeutic responses to chemotherapeutic agents of choriocarcinoma cells. In addition to its role in inhibiting tumor growth, low dose of Ad-PUMA significantly restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents in vitro and in vivo. Exogenous PUMA is potentially useful as a sensitizer in treating drug-resistant choriocarcinoma.

• Adenovirus carrying TIMP-3: A potential tool for cervical cancer treatment

  Authors: Ying Zhang, Haili Qian, Chen Lin, Jinghe Lang, Yang Xiang, Ming Fu, Xueyan Zhang, Xiao Liang

  Gynecologic Oncology.

  Objective.Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit all ofObjective.Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit all of MMPs, and its overexpression can retard many kinds of tumor growth. Especially, a potent bystander effect would make it to be more advisable for treating cervical cancer whose primary growth pattern is to invade adjacent structures. These characters prompted the authors to explore its further applicability in human cervical cancer.Methods.We constructed a replication deficient adenoviral vector carrying TIMP-3 (Ad-TIMP-3). It was transferred into different cervical cancer cell lines in vitro and was injected into the tumor xenografts of nude mice in vivo.Results.Overexpression of TIMP-3 by adenovirus vector arrested cervical cancer cells in G2/M phase. It also promoted growth inhibition of cancer cells by bystander effects. Ad-TIMP-3 infection produced a more potent cell killing effect than Ad-p53 (P < 0.05). A synergic effect was observed when Ad-TIMP-3 and cisplatin (cDDP) were used in combination (D < 1). In vivo, Ad-TIMP-3 could inhibit cervical cancer xenografts growth. Compared with Ad-TIMP-3 and cDDP groups, tumor growth in Ad-TIMP-3 combined with cDDP group was inhibited more significantly (P < 0.05).Conclusion.These findings indicated that Ad-TIMP-3 bear a therapeutic potential for cervical cancer.