Biomedical subjects

Keping Xie

Publications and source records attributed to Keping Xie.

40 records · Page 3Linked to original sources

PubMed2002

Adenovirus-mediated N5 gene transfer inhibits tumor growth and metastasis of human carcinoma in nude mice.

The therapeutic effectiveness of cancer therapy often relies on induction of apoptotic cell death. Gene-therapy-mediated induction of apoptosis, therefore, may provide an effective means to kill cancer cells. The N5 gene encodes a death-domain-containing protein (p84N5) that can trigger atypical apoptosis from within the nucleus, suggesting it may be a candidate for use as a gene therapy for cancer. In the present study, we test the potential utility of a recombinant adenovirus designed to express the N5 gene(AdN5) for the treatment of a variety of human cancers using in vitro and animal models. In vitro, adenoviral-mediated N5 gene transfer inhibits the growth of five different tumor cell lines, but not a normal diploid fibroblast cell line. Adenoviral-mediated N5 gene transfer also reduces the growth and metastasis of primary human tumors in subcutaneous and orthotopic xenograft mouse models. Reduction in tumor cell growth in vitro and in vivo correlates with increased expression of p84N5 and induction of apoptosis. The relative sensitivity of different human cancer cells to AdN5 or Adp53 varies, suggesting that AdN5 may be effective in tumors relatively resistant to p53 gene therapy. We conclude that N5 has potential utility for the gene therapy of cancer.

Adenocarcinoma↗

PubMed2002

The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia.

Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca(2+)) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca(2+) neither induced the HIF-1alpha protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca(2+) induced NDRG-1/Cap43 mRNA in HIF-1alpha-deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca(2+) ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-1/Cap43 gene expression in both human and mouse cells. Using a set of deletion VEGF-Luc promoter constructs, we found that both HIF-1 and two AP-1 sites contribute to hypoxia-mediated induction of transcription. In contrast, only AP-1 sites contributed to Ca(2+)-mediated VEGF-Luc induction. A dominant-negative AP-1 prevented Ca(2+)-dependent transcription and partially impaired hypoxia-mediated transcription. In addition, dominant-negative AP-1 diminished the expression of the NDRG-1/Cap43 gene following hypoxia. We conclude that during hypoxia, an increase in intracellular Ca(2+) activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription. Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia.

Animals↗

PubMed2001

Mouse Models of Metastatic Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma is a deadly disease. Its etiology is unknown, and metastatic disease kills themajority of patients who have it. Effective prevention is clearly the ultimate goal for eradicating this diseaseprovided that the effects of environmental and genetic elements on pancreatic cancer development arefully understood. Currently, it appears that the control of pancreatic cancer metastasis is of immediateurgency. Fulfillment of this difficult task relies on knowledge of the cellular and molecular biology of metastasis.The use of relevant animal models will help define each aspect of this complicated process.

Journal Article↗

PubMed2001

A Novel, Clinically Relevant Animal Model of Metastatic Pancreatic Adenocarcinoma Biology and Therapy.

In this study, we report a metastatic model of Panc02 murine pancreatic adenocarcinoma. Parental Panc02cells were orthotopically implanted into the pancreas of syngeneic C57BL/6 mice. Tumor cells were isolatedfrom liver micrometastases 90 d after tumor implantation and established as a culture (Panc02-H1).The Panc02-H1 cells were then implanted into the pancreas of mice. Liver metastases were then collectedand established as Panc02-H2 cells. This process was repeated until the Panc02-H7 cell line was established.These cells were extremely aggressive after implantation as manifested by progressive growth in the pancreas,peritoneal dissemination, and distant metastasis to multiple organs, including the liver and lungs.Moreover, Panc02-H7 cells expressed the inducible nitric oxide synthase gene at a very low level in cultureand produced highly vascularized tumors having a large number of infiltrating macrophages. Collectively,this model system should be a valuable tool for investigating the molecular mechanisms governing pancreaticcancer growth and metastasis and exploring potential treatment modalities for this disease.

Journal Article↗