F Zhang

Cornell University, Ithaca, NY, United States

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Publications (11)69.76 Total impact

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    ABSTRACT: Reflux of duodenal contents including bile acids is believed to contribute to esophageal injury and Barrett's esophagus. Cyclooxygenase (COX)-2, an inducible form of COX, has been implicated in both inflammation and carcinogenesis. In this study, we investigated the effects of bile acids and duodenal reflux on COX-2 expression in cultured esophageal cells and tissue, respectively. Immunoblotting and Northern blotting were used to assess the effects of bile acids on COX-2 expression in esophageal cell lines. Immunoblotting and immunohistochemistry were performed to evaluate the effects of duodenal reflux on COX-2 expression and cell proliferation in esophageal tissue. Unconjugated bile acids were about fivefold more potent inducers of COX-2 messenger RNA, COX-2 protein, and prostaglandin synthesis than conjugated bile acids. Acidifying the culture medium sensitized esophageal cells to bile acid-mediated induction of COX-2. The induction of COX-2 by bile acids was mediated by phosphatidylinositol-3 kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. In experimental animals, duodenoesophageal reflux led to esophagitis, marked thickening of the esophageal mucosa, and enhanced expression of COX-2. Increased immunoreactivity for Ki-67 and cyclin D1 indicated that enhanced cell proliferation contributed to mucosal thickening. Reflux of duodenal contents into the esophagus led to increased COX-2 expression and mucosal thickening. Bile acids are likely to contribute to these effects.
    Gastroenterology 12/2001; 121(6):1391-9. · 12.82 Impact Factor
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    ABSTRACT: An inducible microsomal form of human prostaglandin E synthase (mPGES) was recently identified. This enzyme converts the cyclooxygenase (COX) product, prostaglandin (PG) H2, to PGE2, a prostanoid that has been implicated in carcinogenesis. Increased amounts of PGE2 are detected in many types of cancer, but the underlying mechanism is not fully understood. Hence, we compared amounts of mPGES in 19 paired samples (tumor and adjacent normal tissue) of non-small cell lung cancer (NSCLC). By immunoblot analysis, mPGES was overexpressed in about 80% of NSCLCs. Immunohistochemistry localized the expression of mPGES to neoplastic epithelial cells. COX-2 was also commonly up-regulated in these tumors; marked differences in the extent of up-regulation of mPGES and COX-2 were observed in individual tumors. Cell culture was used to define the underlying mechanism(s) that accounts for up-regulation of mPGES in NSCLC. As reported previously for COX-2, levels of mPGES mRNA and protein were increased in NSCLC cell lines containing mutant Ras as compared with a nontumorigenic bronchial epithelial cell line. Nuclear run-offs revealed increased rates of mPGES transcription in the transformed cell lines. Overexpression of Ras caused a severalfold increase in mPGES promoter activity in nontransformed cells. Tumor necrosis factor-alpha induced mPGES and COX-2 in NSCLC cell lines but had no effect on the expression of either enzyme in a nontumorigenic bronchial epithelial cell line. Consistent with prior observations for COX-2, these data suggest that both cellular transformation and cytokines contribute to the up-regulation of mPGES in NSCLC.
    Clinical Cancer Research 10/2001; 7(9):2669-74. · 7.84 Impact Factor
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    ABSTRACT: Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.
    Clinical Cancer Research 03/2001; 7(2):429-34. · 7.84 Impact Factor
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    ABSTRACT: The ability of ethanol and arachidonic acid (AA), as inducers of oxidative stress and key factors in alcoholic liver disease, to up-regulate alpha 2 collagen type I (COL1A2) gene expression was studied in a hepatic stellate cell line overexpressing the ethanol-inducible cytochrome P450 2E1 (CYP2E1) (E5 cells). A time- and dose-dependent induction in COL1A2 mRNA by ethanol or AA was observed that was prevented by diallylsulfide, a CYP2E1 inhibitor. Nuclear run-on experiments showed transcriptional activation of the COL1A2 gene by ethanol and AA. Catalase abrogated the increase in COL1A2 mRNA suggesting an H(2)O(2)-dependent mechanism. Cyclooxygenase-2 (COX-2) levels and production of prostaglandin E(2) upon addition of AA were elevated in the E5 cells. Incubation with NS-398, a COX-2 inhibitor, blocked the effect of AA, but not of ethanol, on COL1A2 expression suggesting that CYP2E1 activates COX-2 expression, and the oxidation of AA by COX-2 is responsible for the increase in COL1A2. Activity of a reporter construct driven by -378 base pairs of the proximal promoter region of the COL1A2 gene increased in E5 but not control cells and was further increased by ethanol or AA. These experiments link CYP2E1-dependent oxidative stress to induction of COX-2 and the actions of ethanol and AA on activation of collagen gene expression in hepatic stellate cells.
    Journal of Biological Chemistry 07/2000; 275(26):20136-45. · 4.65 Impact Factor
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    ABSTRACT: Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P) present in tobacco smoke and tar, have been implicated in the development of atherosclerosis as well as cancer. Increased expression of cyclooxygenase-2 (COX-2) has been detected both in atherosclerotic lesions and in epithelial cancers. To determine whether polycyclic aromatic hydrocarbons might directly affect COX expression in vascular cells, we investigated the effects of B[a]P on COX-2 expression in human and rat arterial smooth muscle cells (SMC). Treatment with B[a]P increased levels of COX-2 protein and mRNA and enhanced prostaglandin synthesis. Nuclear runoff assays and transient transfections revealed increased COX-2 gene transcription after treatment with B[a]P. Experiments were done to define the signaling mechanism by which B[a]P induced COX-2. B[a]P caused a rapid increase in phosphorylation of extracellular signal-regulated kinase (ERK); pharmacologic inhibition of mitogen-activated protein kinase kinase blocked B[a]P-mediated induction of COX-2. Depletion of the intracellular antioxidant, glutathione, with buthionine sulfoximine significantly increased B[a]P-mediated induction of COX-2 while exposure to N-acetylcysteine, a precursor of glutathione, suppressed the induction of COX-2 by B[a]P. Several lines of evidence suggest that the induction of COX-2 by B[a]P is mediated, at least in part, by NF-kappaB. Treatment with B[a]P increased binding of NF-kappaB to DNA. Moreover, B[a]P-mediated stimulation of COX-2 promoter activity was blocked when a construct containing a mutagenized NF-kappaB site was used. Pharmacological inhibitors of NF-kappaB blocked the induction of COX-2 protein and the stimulation of COX-2 promoter activity by B[a]P. Taken together, these data are likely to be important for understanding the atherogenic effects of tobacco smoke.
    Journal of Biological Chemistry 03/2000; 275(7):4949-55. · 4.65 Impact Factor
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    ABSTRACT: The purpose of this study was to determine whether cyclooxygenase-2 (COX-2) was overexpressed in squamous cell carcinoma of the head and neck (HNSCC). Quantitative reverse transcription-PCR, immunoblotting, and immunohistochemistry were used to assess the expression of COX-2 in head and neck tissue. Mean levels of COX-2 mRNA were increased by nearly 150-fold in HNSCC (n = 24) compared with normal oral mucosa from healthy volunteers (n = 17). Additionally, there was about a 50-fold increase in amounts of COX-2 mRNA in normal-appearing epithelium adjacent to HNSCC (n = 10) compared with normal oral mucosa from healthy volunteers. Immunoblotting demonstrated that COX-2 protein was present in six of six cases of HNSCC but was undetectable in normal oral mucosa from healthy subjects. Immunohistochemical analysis showed that COX-2 was expressed in both HNSCC and adjacent normal-appearing epithelium. Taken together, these results suggest that COX-2 may be a target for the prevention or treatment of HNSCC.
    Cancer Research 04/1999; 59(5):991-4. · 8.65 Impact Factor
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    ABSTRACT: We investigated whether curcumin, a chemopreventive agent, inhibited chenodeoxycholate (CD)- or phorbol ester (PMA)-mediated induction of cyclooxygenase-2 (COX-2) in several gastrointestinal cell lines (SK-GT-4, SCC450, IEC-18 and HCA-7). Treatment with curcumin suppressed CD- and PMA-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Curcumin also suppressed the induction of COX-2 mRNA by CD and PMA. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with CD or PMA and these effects were inhibited by curcumin. Treatment with CD or PMA increased binding of AP-1 to DNA. This effect was also blocked by curcumin. In addition to the above effects on gene expression, we found that curcumin directly inhibited the activity of COX-2. These data provide new insights into the anticancer properties of curcumin.
    Carcinogenesis 04/1999; 20(3):445-51. · 5.64 Impact Factor
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    ABSTRACT: A large body of evidence suggests that cyclooxygenase-2 (COX-2) is important in gastrointestinal cancer. The purpose of this study was to determine whether COX-2 was expressed in adenocarcinoma of the human pancreas. Quantitative reverse transcription-PCR, immunoblotting, and immunohistochemistry were used to assess the expression of COX-2 in pancreatic tissue. Levels of COX-2 mRNA were increased by >60-fold in pancreatic cancer compared to adjacent nontumorous tissue. COX-2 protein was present in 9 of 10 cases of adenocarcinoma of the pancreas but was undetectable in nontumorous pancreatic tissue. Immunohistochemical analysis showed that COX-2 was expressed in malignant epithelial cells. In cultured human pancreatic cancer cells, levels of COX-2 mRNA and protein were induced by treatment with tumor-promoting phorbol esters. Taken together, these results suggest that COX-2 may be a target for the prevention or treatment of pancreatic cancer.
    Cancer Research 03/1999; 59(5):987-90. · 8.65 Impact Factor
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    ABSTRACT: Cyclooxygenase (COX) catalyzes the formation of prostaglandins (PG) from arachidonic acid. A large body of evidence has accumulated to suggest that COX-2, the inducible form of COX, is important in carcinogenesis. In this study, we determined whether (1) COX-2 was overexpressed in squamous cell carcinoma of the head and neck (HNSCC) and whether (2) retinoids, a class of chemopreventive agents, blocked epidermal growth factor (EGF)-mediated activation of COX-2 expression. Levels of COX-2 mRNA were determined in 15 cases of HNSCC and 10 cases of normal oral mucosa. Nearly a 100-fold increase in amounts of COX-2 mRNA was detected in HNSCC. By immunoblot analysis, COX-2 protein was detected in 6 of 6 cases of HNSCC but was undetectable in normal mucosa. Because retinoids protect against oral cavity cancer, we investigated whether retinoids could suppress EGF-mediated induction of COX-2 in cultured oral squamous carcinoma cells. Treatment with EGF led to increased levels of COX-2 mRNA, COX-2 protein, and synthesis of PG. These effects were suppressed by a variety of retinoids. Based on the results of this study, it will be important to establish whether newly developed selective COX-2 inhibitors are useful in preventing or treating HNSCC. Moreover, the anticancer properties of retinoids may be due, in part, to inhibition of COX-2 expression. Combining a retinoid with a selective COX-2 inhibitor may be more effective than either agent alone in preventing cancer of the upper aerodigestive tract.
    Annals of the New York Academy of Sciences 02/1999; 889:62-71. · 4.38 Impact Factor
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    ABSTRACT: Bile acids, endogenous promoters of gastrointestinal cancer, activate protein kinase C (PKC) and the activator protein-1 (AP-1) transcription factor. Because other activators of PKC and AP-1 induce cyclooxygenase-2 (COX-2), we determined the effects of bile acids on the expression of COX-2 in human esophageal adenocarcinoma cells. Treatment with the dihydroxy bile acids chenodeoxycholate and deoxycholate resulted in an approximately 10-fold increase in the production of prostaglandin E2 (PGE2). Enhanced synthesis of PGE2 was associated with a marked increase in the levels of COX-2 mRNA and protein, with maximal effects at 8-12 and 12-24 h, respectively. In contrast, neither cholic acid nor conjugated bile acids affected the levels of COX-2 or the synthesis of PGE2. Nuclear run-off assays and transient transfections with a human COX-2 promoter construct showed that induction of COX-2 mRNA by chenodeoxycholate and deoxycholate was due to increased transcription. Bile acid-mediated induction of COX-2 was blocked by inhibitors of PKC activity, including calphostin C and staurosporine. Treatment with bile acid enhanced the phosphorylation of c-Jun and increased binding of AP-1 to DNA. These data are important because dihydroxy bile acid-mediated induction of COX-2 may explain, at least in part, the tumor-promoting effects of bile acids.
    Journal of Biological Chemistry 02/1998; 273(4):2424-8. · 4.65 Impact Factor

Publication Stats

1k Citations
69.76 Total Impact Points

Institutions

  • 2001
    • Cornell University
      • Cardiothoracic Surgery
      Ithaca, NY, United States
    • New York Presbyterian Hospital
      • Department of Pain Medicine
      New York City, New York, United States
  • 1999
    • Weill Cornell Medical College
      • Department of Cardiothoracic Surgery
      New York City, New York, United States