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  1. Article ; Online: Twist2 is NFkB-responsive when p120-catenin is inactivated and EGFR is overexpressed in esophageal keratinocytes

    Heather L. Lehman / Michal Kidacki / Douglas B. Stairs

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 12

    Abstract: Abstract Esophageal squamous cell carcinoma (ESCC) is among the most aggressive and fatal cancer types. ESCC classically progresses rapidly and frequently causes mortality in four out of five patients within two years of diagnosis. Yet, little is known ... ...

    Abstract Abstract Esophageal squamous cell carcinoma (ESCC) is among the most aggressive and fatal cancer types. ESCC classically progresses rapidly and frequently causes mortality in four out of five patients within two years of diagnosis. Yet, little is known about the mechanisms that make ESCC so aggressive. In a previous study we demonstrated that p120-catenin (p120ctn) and EGFR, two genes associated with poor prognosis in ESCC, work together to cause invasion. Specifically, inactivation of p120ctn combined with overexpression of EGFR induces a signaling cascade that leads to hyperactivation of NFkB and a resultant aggressive cell type. The purpose of this present study was to identify targets that are responsive to NFkB when p120ctn and EGFR are modified. Using human esophageal keratinocytes, we have identified Twist2 as an NFkB-responsive gene. Interestingly, we found that when NFkB is hyperactivated in cells with EGFR overexpression and p120ctn inactivation, Twist2 is significantly upregulated. Inhibition of NFkB activity results in nearly complete loss of Twist2 expression, suggesting that this potential EMT-inducing gene, is a responsive target of NFkB. There exists a paucity of research on Twist2 in any cancer type; as such, these findings are important in ESCC as well as in other cancer types.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Loss of p120ctn causes EGFR-targeted therapy resistance and failure.

    Mary E Landmesser / Wesley M Raup-Konsavage / Heather L Lehman / Douglas B Stairs

    PLoS ONE, Vol 15, Iss 10, p e

    2020  Volume 0241299

    Abstract: Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a ... ...

    Abstract Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a prime candidate as a therapeutic target. While targeted EGFR therapy is initially effective in 75% of patients, a majority of patients relapse within the first year due to poorly understood mechanisms of resistance. p120-catenin (p120ctn) has recently been implicated as a biomarker for EGFR therapy. In previous studies, we demonstrated that p120ctn is a tumor suppressor and its loss is capable of inducing cancer. Furthermore, p120ctn down-regulation synergizes with EGFR overexpression to cause a highly invasive cell phenotype. The purpose of this present study was to investigate whether p120ctn down-regulation induced EGFR therapeutic resistance. Using human esophageal keratinocytes, we have found that EGFR-targeting compounds are toxic to cells overexpressing EGFR. Interestingly, these therapies do not cause toxicity in cells with EGFR overexpression and decreased p120ctn expression. These data suggest that decreased p120ctn causes resistance to EGFR therapy. We believe these findings are of utmost importance, as there is an unmet need to discover mechanisms of EGFR resistance.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Black raspberry restores the expression of the tumor suppressor p120ctn in the oral cavity of mice treated with the carcinogen dibenzo[a,l]pyrene diol epoxide.

    Douglas B Stairs / Mary E Landmesser / Cesar Aliaga / Kun-Ming Chen / Yuan-Wan Sun / Karam El-Bayoumy

    PLoS ONE, Vol 16, Iss 11, p e

    2021  Volume 0259998

    Abstract: One of the major risk factors for head and neck squamous cell carcinoma (HNSCC) is tobacco smoke exposure, but the mechanisms that can account for disease development remain to be fully defined. Utilizing our HNSCC mouse model, we analyzed oral squamous ... ...

    Abstract One of the major risk factors for head and neck squamous cell carcinoma (HNSCC) is tobacco smoke exposure, but the mechanisms that can account for disease development remain to be fully defined. Utilizing our HNSCC mouse model, we analyzed oral squamous cell carcinomas (OSCC) induced by the active metabolite of a common smoke constituent, dibenzo[a,l]pyrene diol-epoxide (DBPDE). Analyzing protein expression by either immunofluorescence or immunohistochemistry, we identified biologic processes that are dysregulated in premalignant and invasive cancer lesions induced by DBPDE. Interestingly, p120ctn expression is downregulated in both stages of the disease. In addition to decreased p120ctn expression, there was also increased proliferation (as measured by Ki67), inflammation (as measured by NFkB (p65) expression), neovascularization (as measured by CD31) and recruitment of Ly6G-positive immune cells as well as strong EGFR expression. We also examined the effect of the chemopreventive agent black raspberry (BRB) on p120ctn and EGFR protein expression in DBPDE treated mice. p120ctn, but not EGFR, protein expression increased in mice treated with BRB. Our results suggest that modulation of p120ctn may, in part, account for the mechanism by which BRB inhibits DBPDE induced OSCC in mice.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Black raspberry restores the expression of the tumor suppressor p120ctn in the oral cavity of mice treated with the carcinogen dibenzo[a,l]pyrene diol epoxide

    Douglas B. Stairs / Mary E. Landmesser / Cesar Aliaga / Kun-Ming Chen / Yuan-Wan Sun / Karam El-Bayoumy

    PLoS ONE, Vol 16, Iss

    2021  Volume 11

    Abstract: One of the major risk factors for head and neck squamous cell carcinoma (HNSCC) is tobacco smoke exposure, but the mechanisms that can account for disease development remain to be fully defined. Utilizing our HNSCC mouse model, we analyzed oral squamous ... ...

    Abstract One of the major risk factors for head and neck squamous cell carcinoma (HNSCC) is tobacco smoke exposure, but the mechanisms that can account for disease development remain to be fully defined. Utilizing our HNSCC mouse model, we analyzed oral squamous cell carcinomas (OSCC) induced by the active metabolite of a common smoke constituent, dibenzo[a,l]pyrene diol-epoxide (DBPDE). Analyzing protein expression by either immunofluorescence or immunohistochemistry, we identified biologic processes that are dysregulated in premalignant and invasive cancer lesions induced by DBPDE. Interestingly, p120ctn expression is downregulated in both stages of the disease. In addition to decreased p120ctn expression, there was also increased proliferation (as measured by Ki67), inflammation (as measured by NFkB (p65) expression), neovascularization (as measured by CD31) and recruitment of Ly6G-positive immune cells as well as strong EGFR expression. We also examined the effect of the chemopreventive agent black raspberry (BRB) on p120ctn and EGFR protein expression in DBPDE treated mice. p120ctn, but not EGFR, protein expression increased in mice treated with BRB. Our results suggest that modulation of p120ctn may, in part, account for the mechanism by which BRB inhibits DBPDE induced OSCC in mice.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: PIGN spatiotemporally regulates the spindle assembly checkpoint proteins in leukemia transformation and progression

    Emmanuel K. Teye / Shasha Lu / Fangyuan Chen / Wenrui Yang / Thomas Abraham / Douglas B. Stairs / Hong-Gang Wang / Gregory S. Yochum / Robert A. Brodsky / Jeffrey J. Pu

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 13

    Abstract: Abstract Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) has been linked to the suppression of chromosomal instability. The spindle assembly checkpoint complex is responsible for proper chromosome segregation during mitosis to prevent ... ...

    Abstract Abstract Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) has been linked to the suppression of chromosomal instability. The spindle assembly checkpoint complex is responsible for proper chromosome segregation during mitosis to prevent chromosomal instability. In this study, the novel role of PIGN as a regulator of the spindle assembly checkpoint was unveiled in leukemic patient cells and cell lines. Transient downregulation or ablation of PIGN resulted in impaired mitotic checkpoint activation due to the dysregulated expression of spindle assembly checkpoint-related proteins including MAD1, MAD2, BUBR1, and MPS1. Moreover, ectopic overexpression of PIGN restored the expression of MAD2. PIGN regulated the spindle assembly checkpoint by forming a complex with the spindle assembly checkpoint proteins MAD1, MAD2, and the mitotic kinase MPS1. Thus, PIGN could play a vital role in the spindle assembly checkpoint to suppress chromosomal instability associated with leukemic transformation and progression.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Barrett’s Esophagus

    Atul Bhardwaj / Thomas J. McGarrity / Douglas B. Stairs / Haresh Mani

    Pathology Research International, Vol

    Emerging Knowledge and Management Strategies

    2012  Volume 2012

    Keywords Pathology ; RB1-214 ; Medicine ; R ; DOAJ:Pathology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Cox2 and β-Catenin/T-cell Factor Signaling Intestinalize Human Esophageal Keratinocytes When Cultured under Organotypic Conditions

    Jianping Kong / Mary Ann S. Crissey / Douglas B. Stairs / Antonia R. Sepulveda / John P. Lynch

    Neoplasia : An International Journal for Oncology Research, Vol 13, Iss 9, Pp 792-

    2011  Volume 805

    Abstract: The incidence of esophageal adenocarcinoma (EAC) is rising in the United States. An important risk factor for EAC is the presence of Barrett esophagus (BE). BE is the replacement of normal squamous esophageal epithelium with a specialized columnar ... ...

    Abstract The incidence of esophageal adenocarcinoma (EAC) is rising in the United States. An important risk factor for EAC is the presence of Barrett esophagus (BE). BE is the replacement of normal squamous esophageal epithelium with a specialized columnar epithelium in response to chronic acid and bile reflux. However, the emergence of BE from squamous keratinocytes has not yet been demonstrated. Our research has focused on this. Wnt and cyclooxygenase 2 (Cox2) are two pathways whose activation has been associated with BE and progression to EAC, but their role has not been tested experimentally. To explore their contribution, we engineered a human esophageal keratinocyte cell line to express either a dominant-active Wnt effector CatCLef or a Cox2 complementary DNA. In a two-dimensional culture environment, Cox2 expression increases cell proliferation and migration, but neither transgene induces known BE markers. In contrast, when these cells were placed into three-dimensional organotypic culture conditions, we observed more profound effects. CatCLef-expressing cells were more proliferative, developed a thicker epithelium, and upregulated Notch signaling and several BE markers including NHE2. Cox2 expression also increased cell proliferation and induced a thicker epithelium. More importantly, we observed cysts form within the epithelium, filled with intestinal mucins including Muc5B and Muc17. This suggests that Cox2 expression in a three-dimensional culture environment induces a lineage of mucin-secreting cells and supports an important causal role for Cox2 in BE pathogenesis. We conclude that in vitro modeling of BE pathogenesis can be improved by enhancing Wnt signaling and Cox2 activity and using three-dimensional organotypic culture conditions.
    Keywords Medicine ; R ; Internal medicine ; RC31-1245 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Subject code 570
    Publishing date 2011-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus.

    Douglas B Stairs / Hiroshi Nakagawa / Andres Klein-Szanto / Shukriyyah D Mitchell / Debra G Silberg / John W Tobias / John P Lynch / Anil K Rustgi

    PLoS ONE, Vol 3, Iss 10, p e

    2008  Volume 3534

    Abstract: Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are ... ...

    Abstract Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are typically associated with the stratified squamous epithelium chronically exposed to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and Barrett's esophagus, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes have remained undefined.To begin to identify the genetic changes responsible for transdifferentiaiton in Barrett's esophagus, we performed a microarray analysis of normal esophageal, Barrett's esophagus and small intestinal biopsy specimens to identify candidate signaling pathways and transcription factors that may be involved. Through this screen we identified the Cdx1 homeodomain transcription factor and the c-myc pathway as possible candidates. Cdx1 and c-myc were then tested for their ability to induce transdifferentiation in immortalized human esophageal keratinocytes using organotypic culturing methods. Analyses of these cultures reveal that c-myc and cdx1 cooperate to induce mucin production and changes in keratin expression that are observed in the epithelium of Barrett's esophagus.These data demonstrate the ability of Cdx1 and c-myc to initiate the earliest stages of transdifferentiation of esophageal keratinocytes toward a cell fate characteristic of Barrett's esophagus.
    Keywords Medicine ; R ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2008-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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