Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120-catenin with the cytoplasmic tail of MUC1.

Adherens junctions (AJs) containing epithelial cadherin (E-cad) bound to p120-catenin (p120ctn) and β-catenin (β-ctn) play a crucial role in regulating cell-cell adhesion. Cigarette smoke abrogates cell-cell adhesion between epithelial cells by disrupting E-cad, a hallmark of epithelial-mesenchymal transition (EMT), yet the underlying mechanism remains unknown. We used an organotypic culture of primary human bronchial epithelial (HBE) cells treated with smoke-concentrated medium (Smk) to establish an essential role for the interaction between p120ctn and the cytoplasmic tail of MUC1 (MUC1-CT) in regulating E-cad disruption.

TACE/ADAM-17 phosphorylation by PKC-epsilon mediates premalignant changes in tobacco smoke-exposed lung cells.

Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecular events responsible for this are poorly understood. We recently showed that signaling mechanisms triggered by smoke in lung cells could lead to the activation of a growth factor signaling pathway, thereby promoting hyperproliferation of lung epithelial cells. Hyperproliferation is considered a premalignant change in the lung, in that increased rates of DNA synthesis are associated with an increased number of DNA copying errors, events that are exacerbated in the presence of tobacco smoke carcinogens.

EMMPRIN regulates the canonical Wnt/beta-catenin signaling pathway, a potential role in accelerating lung tumorigenesis.

Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/beta-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors.

Leukotriene D4 upregulates MUC2 gene transcription in human epithelial cells.

Background/aims: Leukotriene (LT) D(4) has been shown to induce mucus secretion in the airways. Excessive mucus secretion characterizes airway inflammatory disease such as asthma, allergic rhinitis. However, little is known about the effect of LTD(4) on mucin gene expression.

Exposure of human corneal epithelial cells to contact lenses in vitro suppresses the upregulation of human beta-defensin-2 in response to antigens of Pseudomonas aeruginosa.

Bacterial keratitis is a sight-threatening complication of contact lens wear, and Pseudomonas aeruginosa is a commonly isolated pathogen. The mechanisms by which lenses predispose the cornea to P. aeruginosa infection are unknown.

Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer.

Background: Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood.

Methodology/principal Findings: Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice.

MUC5AC mucin gene regulation in pancreatic cancer cells.

MUC5AC is a secretory mucin normally expressed by the surface mucous cells of the human stomach and in the bronchial tract. It is absent from normal pancreas, but de novo expression of this mucin occurs in early-stage pancreatic intraepithelial neoplasias and in the invasive ductal adenocarcinoma of the pancreas, prompting this study of MUC5AC gene regulation in pancreatic cancer cells. Promoter deletion constructs and EMSA studies revealed that transcription factors Sp1 and AP-1 are both involved in basal transcription of the MUC5AC gene.

AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2.

Bacterial flagellin can interact with both Toll-like receptor 5 (TLR5) and the cell surface glycolipid, asialoGM1, to activate an innate immune response. The induction of mucin by flagellin in human lung epithelial cells (NCIH292) is dependent on asialoGM1 ligation, ATP receptor signaling, Ca2+ mobilization, and Erk1/2 activation. Conversely, the activation of NF-kappaB by flagellin is dependent on signaling through TLR5.

Immune complex-dependent remodeling of the airway vasculature in response to a chronic bacterial infection.

Chronic inflammation in the airways is associated with dramatic architectural changes in the walls of the airways and in the vasculature they contain. In this study, we show that the adaptive immune system is essential for airway remodeling that occurs in mice that are chronically infected with the respiratory pathogen Mycoplasma pulmonis. Angiogenesis, lymphangiogenesis, and epithelial remodeling were greatly reduced in mice that lacked B cells.

New HIV-drug inhibits in vitro bladder cancer migration and invasion.

Objective: The CXCR4/CXCL12 axis appears crucial in the metastasis of bladder cancer. Our aim was to evaluate the potency of the CXCR4 antagonist, 4F-benzoyl-TE14011 (4F-bTE), as an anti-metastatic drug in this disease. In this study, we assessed the ability of 4F-bTE to inhibit tumor cell motility, invasion through extracellular matrix (ECM), matrix metalloproteinase (MMP) secretion and cytoskeletal responses to chemokine.

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells.

Transitional cell carcinoma of the urinary bladder remains life threatening due to the high occurrence of metastases. Emerging evidence suggests that chemokines and their receptors play a critical role in tumor metastases. In our study, we performed a systematic analysis of the mRNA and protein expression levels of all 18 chemokine receptors in normal urothelium and bladder cancer.

Sp1 is involved in the transcriptional activation of lysozyme in epithelial cells.

Lysozyme protects us from the ever-present danger of bacterial infection. The expression of lysozyme is, in part, regulated by the Ets factor, myeloid elf-1-like factor (MEF). MEF binds to the ETS site of the lysozyme promoter at -46 to -40bp.

Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways.

Mucin overproduction is a hallmark of nontypeable Haemophilus influenzae (NTHi) infections. The molecular mechanisms underlying up-regulation of mucin in NTHi infections especially during the initial phase remain unknown. Here we show that P6, a 16-kDa outer membrane lipoprotein well conserved in NTHi, up-regulates MUC5AC mucin gene transcription in vitro and in vivo.

Pranlukast inhibits NF-kappaB activation and MUC2 gene expression in cultured human epithelial cells.

Pranlukast is a selective cysteinyl leukotriene(1 )(cysLT(1)) receptor antagonist, and is now widely used in the treatment of asthma. The anti-asthmatic effect of pranlukast may be rendered not only by antileukotriene activity, but also by other pharmacological activity. This study was designed to investigate whether pranlukast had inhibitory effects on nuclear factor-kappaB (NF-kappaB) activation and mucin gene expression in cultured human epithelial cells.

Adenosine up-regulation of the mucin gene, MUC2, in asthma.

Mucus hypersecretion is a hallmark of asthma that contributes to airway obstruction. While the etiology is not well understood, hypersecretion has been linked to the presence of cytokines such as IL-4, IL-5, IL-9, and IL-13 in the inflamed airway. The presence of adenosine has also been noted in asthmatic airways, and adenosine-mediated signaling in mast cells has been implicated in the severe bronchoconstriction and inflammation prevalent in these patients (1, 2).

Roxithromycin suppresses mucin gene expression in epithelial cells.

Macrolide antibiotics are believed to inhibit mucus secretion but the mechanism of action is unclear. This study was designed to investigate an effect of roxithromycin on MUC2 gene expression in cultured intestinal epithelial cells (HM3-MUC2 cells). A reporter gene assay was used for analysis.

Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK.

In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined.

Detection of occult tumor cells in lymph nodes from bladder cancer patients by MUC7 nested RT-PCR.

Objective: Systemic progression is the prevalent form of bladder tumor recurrence after radical cystectomy. The detection of occult bladder tumor cells in histopathologically normal lymph nodes could be of prognostic value. We examined the possibility that mucin 7 (MUC7) RNA might reflect the presence of occult tumor cells in lymph nodes from bladder cancer patients.

The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions.

EMMPRIN is a transmembrane glycoprotein expressed at high levels by tumor cells. It has been identified as a tumor-derived factor that can stimulate matrix metalloproteinase expression in fibroblasts and hence facilitate tumor invasion and metastasis. Recent studies have shown that full-length EMMPRIN is released by tumor cells, but the mechanism of release remains unclear.

Viral dsRNA activates mucin transcription in airway epithelial cells.

Double-stranded (ds) RNA is a biologically active component of many viruses including rhinoviruses infecting the upper respiratory tract. Mucus production is a common symptom of such infections. Here, we show that mucin, the glycoprotein subunit of mucus gels, is transcriptionally upregulated in an NF-kappaB- and p38-dependent manner when homogeneous cultures of epithelial cells are exposed to dsRNA.

Toxicity of chemical components of fine particles inhaled by aged rats: effects of concentration.

This study tested the hypothesis that exposure to mixtures containing fine particles and ozone (O3) would cause pulmonary injury and decrements in functions of immunological cells in exposed rats (22-24 months old) in a dose-dependent manner. Rats were exposed to high and low concentrations of ammonium bisulfate and elemental carbon and to 0.2 ppm O3.

Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin.

Cells dividing at the time of carcinogen exposure are at particular risk for neoplasia. Tobacco smoke contains numerous carcinogens, and we find that smoke, in the absence of exogenous growth factors, is capable of stimulating cell proliferation. The smoke-triggered mechanism includes the generation of oxygen radicals, which in turn stimulate tumor necrosis factor alpha-converting enzyme (a disintegrin and metalloproteinase (ADAM) 17) to cleave transmembrane amphiregulin, a ligand for the epidermal growth factor receptor (EGFR).

Mechanisms by which gram-positive bacteria and tobacco smoke stimulate mucin induction through the epidermal growth factor receptor (EGFR).

Mucin, the major macromolecular component of mucus, is generally considered to be a protective substance. When overproduced in a variety of lung diseases, however, mucin gives rise to clinical problems such as airway obstruction and recurrent infection. Our approach to identifying drug targets for the control of mucin overproduction is the analysis of cellular signalling pathways linking stimuli in the diseased lung to mucin transcription.