Xiufen Li

Honolulu University, Honolulu, Hawaii, United States

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Publications (15)156.55 Total impact

  • Gastroenterology 04/2015; 148(4):S-576. DOI:10.1016/S0016-5085(15)31945-4 · 16.72 Impact Factor
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    ABSTRACT: The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-Butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells, which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogs of 1 in order to improve the efficacy and pharmaceutical properties. Analogs and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogs identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer spread in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.
    Journal of Medicinal Chemistry 01/2015; 58(3). DOI:10.1021/jm501437v · 5.45 Impact Factor
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    ABSTRACT: We previously found that conditional deletion of integrin β1 in intestinal epithelium of mice caused early postnatal lethality and intestinal phenotypic changes including excessive proliferation and defective differentiation of intestinal epithelium due to loss of Hedgehog expression. Here, we link these defects to the Hedgehog (Hh) signaling pathway and show that loss of integrin β1 leads to excessive phosphorylation of MEK-1 and increased expression of ErbB receptors, including the epidermal growth factor receptor (EGFR). We show that increased EGFR signaling attenuates Hh abundance and that an EGFR inhibitor rescues conditional β1 integrin null pups from postnatal lethality. These studies link the loss of Hh expression in the intestinal epithelium of integrin β1-deficient mice to excessive EGFR/MAPK signaling, and identify a unique mechanism for crosstalk between stromal and epithelial signaling pathways that is critical for intestinal epithelial differentiation and function. © 2014 IUBMB Life, 2014
    International Union of Biochemistry and Molecular Biology Life 10/2014; 66(10). DOI:10.1002/iub.1319 · 3.14 Impact Factor
  • Yi Shen · Xiufen Li · Xuegang Lao · Scott K. Kuwada ·

    Gastroenterology 05/2014; 146(5):S-811-S-812. DOI:10.1016/S0016-5085(14)62934-6 · 16.72 Impact Factor
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    ABSTRACT: Because HER-2 has been demonstrated in the nuclei of cancer cells, we hypothesized that it might interact with transcription factors that activate ERBB2 transcription. Macrohistone 2A1 (H2AFY; mH2A1) was found to interact with HER-2 in cancer cells that overexpress HER-2. Of the two human mH2A1 isoforms, mH2A1.2, but not mH2A1.1, interacted with HER-2 in human cancer cell lines. Overexpression of mH2A1.2, but not mH2A1.1, in cancer cells significantly increased HER-2 expression and tumorigenicity. Inhibition of HER-2 kinase activity diminished mH2A1 expression and mH2A1.2-induced ERBB2 transcription in cancer cells. Chromatin immunoprecipitation of mH2A1.2 in cancer cells stably transfected with mH2A1.2 showed enrichment of mH2A1.2 at the HER-2 promoter, suggesting a role for mH2A1.2 in driving HER-2 overexpression. The evolutionarily conserved macro domain of mH2A1.2 was sufficient for the interaction between HER-2 and mH2A1.2 and for mH2A1.2-induced ERBB2 transcription. Within the macro domain of mH2A1.2, a trinucleotide insertion (-EIS-) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation.
    Journal of Biological Chemistry 05/2012; 287(27):23171-83. DOI:10.1074/jbc.M112.379412 · 4.57 Impact Factor
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    ABSTRACT: The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal carcinomatosis in mice.(1,2) In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.
    Bioorganic & medicinal chemistry letters 03/2012; 22(5):1850-3. DOI:10.1016/j.bmcl.2012.01.085 · 2.42 Impact Factor

  • Gastroenterology 05/2009; 136(5). DOI:10.1016/S0016-5085(09)61802-3 · 16.72 Impact Factor

  • Gastroenterology 04/2008; 134(4). DOI:10.1016/S0016-5085(08)60218-8 · 16.72 Impact Factor
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    ABSTRACT: Conditional deletion of beta1 integrins in the intestinal epithelium, unlike in epidermal and mammary epithelia, of mice does not result in decreased cell adhesion and proliferation, but instead causes a profound increase in epithelial proliferation with dysplasia and polypoid structures. The increased epithelial proliferation inhibited epithelial differentiation that caused severe malnutrition and early postnatal lethality. The striking similarities between beta1 integrin-deleted mice and neonatal mice with defective Hedgehog signaling led to the discovery that Hedgehog expression was markedly reduced in the former mice. beta1 integrins were found to drive the expression of Hedgehogs in intestinal epithelial cells in an HNF-3beta (Foxa2)-dependent fashion. The expression of Tcf-4, a transcription factor known to be required for intestinal epithelial stem cell proliferation, was increased and mislocalized in the intestinal epithelia of the beta1 integrin-deleted mice and in newborn mice treated with the Hedgehog signaling inhibitor cyclopamine. This study shows that beta1 integrins are key regulators of proliferation and homeostasis in the intestine and achieve this not through anchorage-dependent effects but by generating Hh expression and signaling.
    The Journal of Cell Biology 12/2006; 175(3):505-14. DOI:10.1083/jcb.200602160 · 9.83 Impact Factor
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    Scott K Kuwada · Jinqiu Kuang · Xiufen Li ·
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    ABSTRACT: HER-2 is constitutively activated and overexpressed in many cancers, and its inhibition in colon cancer cells diminishes tumorigenicity and induces apoptosis. Little is known about the regulation of HER-2 signaling in colon cancer cells. Integrin alpha5/beta1 expression is frequently lost in colorectal cancer cells compared with normal intestinal epithelium, and colon cancer cells lacking integrin alpha5/beta1 expression utilize HER-2 signaling for proliferation and tumorigenicity. Re-expression of integrin alpha5/beta1 in colon cancer cells abrogated their tumorigenicity, but how this occurs is not well known. Stable expression of integrin alpha5/beta1 in colon cancer cells with little or no detectable integrin alpha5/beta1 protein expression resulted in the post-transcriptional down-regulation of HER-2 protein. Integrin alpha5/beta1 was found to interact with HER-2, and the cytoplasmic domain of integrin alpha5/beta1 was sufficient to mediate HER-2 down-regulation. Integrin alpha5/beta1-mediated down-regulation of HER-2 was the result of increased lysosomal targeting. The inhibition of HER-2 signaling represents a potential mechanism by which integrin alpha5/beta1 exerts its tumor suppressor-like activity in colon cancer cells. These results also suggest that a novel function for integrin alpha5/beta1 is the control of HER-2 expression.
    Journal of Biological Chemistry 06/2005; 280(19):19027-35. DOI:10.1074/jbc.M410540200 · 4.57 Impact Factor
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    ABSTRACT: Little information is available as to the potential role of HER-2 as a therapeutic target in colon cancers, which express much fewer HER-2 receptors than breast cancer cells. Treatment of certain human colon cancer cell lines with the HER-2 inhibitory antibody mAb 4D5 demonstrated a role for HER-2 in mediating proliferation, apoptosis and tumorigenicity. However, only the cell lines that were dependent on autocrine EGFR-mediated cell proliferation were susceptible to the antiproliferative and antitumorigenic effects of HER-2 inhibition. The relative levels of HER-2, EGFR, HER-3 and HER-4 were not predictive of responsiveness to mAb 4D5. Treatment with HER-2 antibodies caused a decrease in HER-2 protein levels in all of the colon cancer cell lines and also significantly decreased EGFR levels but only in the EGFR-dependent cell lines. Treatment with mAb 4D5 caused the rapid ubiquitination and ligand-dependent downregulation of the EGFR in an EGFR-dependent colon cancer cell line. Treatment of athymic mice engrafted with EGFR-dependent colon cancer cells with mAb 4D5 caused tumor regression and a decrease in EGFR tyrosine phosphorylation in the tumor cells. EGFR-independent colon cancer cell xenografts were resistant to mAb 4D5 therapy. Combined inhibition of HER-2 and EGFR caused large areas of necrosis in EGFR-dependent colon cancer xenografts, suggesting a benefit of combined HER-2 and EGFR inhibitor therapy. Predicting clinical responsiveness of human colon cancer cells to anti-HER-2 and anti-EGFR therapy may require demonstration of EGFR tyrosine kinase dependency of the cells.
    International Journal of Cancer 03/2004; 109(2):291-301. DOI:10.1002/ijc.11686 · 5.09 Impact Factor
  • Scott K. Kuwada · Jinqui Kuang · Xiufen Li · Robert Wong ·

    Gastroenterology 04/2003; 124(4). DOI:10.1016/S0016-5085(03)81413-0 · 16.72 Impact Factor
  • Robert F. Wong · Jinqiu Kuang · Xiufen Li · Scott Kuwada ·

    Gastroenterology 04/2003; 124(4). DOI:10.1016/S0016-5085(03)80282-2 · 16.72 Impact Factor
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    Scott K. Kuwada · Xiufen Li ·
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    ABSTRACT: Human integrin alpha5 was transfected into the integrin alpha5/beta1-negative intestinal epithelial cell line Caco-2 to study EGF receptor (EGFR) and integrin alpha5/beta1 signaling interactions involved in epithelial cell proliferation. On uncoated or fibronectin-coated plastic, the integrin alpha5 and control (vector only) transfectants grew at similar rates. In the presence of the EGFR antagonistic mAb 225, the integrin alpha5 transfectants and controls were significantly growth inhibited on plastic. However, when cultured on fibronectin, the integrin alpha5 transfectants were not growth inhibited by mAb 225. The reversal of mAb 225-mediated growth inhibition on fibronectin for the integrin alpha5 transfectants correlated with activation of the EGFR, activation of MAPK, and expression of proliferating cell nuclear antigen. EGFR kinase activity was necessary for both MAPK activation and integrin alpha5/beta1-mediated cell proliferation. Although EGFR activation occurred when either the integrin alpha5-transfected or control cells were cultured on fibronectin, coprecipitation of the EGFR with SHC could be demonstrated only in the integrin alpha5-transfected cells. These results suggest that integrin alpha5/beta1 mediates fibronectin-induced epithelial cell proliferation through activation of the EGFR.
    Molecular Biology of the Cell 08/2000; 11(7):2485-96. DOI:10.1091/mbc.11.7.2485 · 4.47 Impact Factor
  • Scott K. Kuwada · Xiufen Li ·

    Gastroenterology 04/2000; 118(4). DOI:10.1016/S0016-5085(00)84274-2 · 16.72 Impact Factor

Publication Stats

213 Citations
156.55 Total Impact Points


  • 2012-2015
    • Honolulu University
      Honolulu, Hawaii, United States
    • University of Hawaiʻi at Mānoa
      • Department of Medicine
      Honolulu, Hawaii, United States
  • 2004-2006
    • University of Utah
      • • Department of Pathology
      • • School of Medicine
      Salt Lake City, Utah, United States