Mucin hypersecretion is commonly observed in many inflammatory diseases of the respiratory tract. MUC5AC is generally recognized to be a major airway mucin because MUC5AC is highly expressed in the goblet cells of human airway epithelium. Moreover, it is regulated by various inflammatory cytokines. However, the mechanisms by which the interleukin ( Mucin hypersecretion is commonly observed in many respiratory diseases, such as rhinitis, sinusitis, otitis media, nasal allergy, chronic bronchitis, and cystic fibrosis (1-4). Eighteen types of mucin genes have been discovered to date: MUC1 (5),

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Vitamin A (retinol) is essential for normal regulation of cell growth and differentiation. We have shown that the retinol metabolite retinoic acid (RA) induces mucous cell differentiation of normal human tracheobronchial epithelial (NHTBE) cells. However, early biological effects of RA in the differentiation of bronchial epithelia are largely unknown. Here, we showed that RA rapidly activated cAMP response element-binding protein (CREB). However, RA did not use the conventional retinoic acid receptor (RAR)/retinoid X receptor (RXR) to activate CREB. RA activated CREB in NHTBE and H1734 cells in which RARs/RXR were silenced with small interfering RNA (siRNA) targeting RAR/RXR expression or deactivated by antagonist. Inhibition of protein kinase C (PKC) or extracellular regulated kinase (ERK1/2) blocked the RA-mediated activation of CREB. In addition, depletion of p90 ribosomal S6 kinase (RSK) via siRSK1/2 completely abolished the activation, suggesting that PKC, ERK, and RSK are required for the activation. Altogether, this study provides the first evidence that RA rapidly activates CREB transcription factor via PKC, ERK, and RSK in a retinoid receptor-independent manner in normal bronchial epithelial cells. This noncanonical RA signaling pathway may play an important role in mediating early biological effects in the mucociliary differentiation of bronchial epithelia. INTRODUCTIONVitamin A (retinol) and its related analogs, collectively called retinoids, play a pivotal role in cell growth and differentiation (for review, see Gudas et al., 1994). In the respiratory system, retinoic acid (RA), the natural metabolite of vitamin A, controls the development and maintenance of differentiated mucociliary epithelial cells. It has been well documented that RA is essential for induction and maintenance of normal mucociliary airway epithelium (McDowell et al., 1984a(McDowell et al., , 1984b. RA deficiency causes squamous metaplasia, and supplementation with RA restores the normal mucous cell phenotype in cultured primary bronchial epithelial cells (Koo et al., 1999). However, the early effect of RA on mucous cell differentiation of bronchial epithelia is largely unknown.It has been well documented that the effects of RA at the genomic level are mediated mainly through heterodimerized forms of retinoid receptors, RARs and RXRs, which recognize expression of their target genes through the RA response element (A/G)G(G/T)TCA upon binding of RA and activate gene expression (Giguere, 1994;Mangelsdorf and Evans, 1995;Chambon, 1996). Recent data showed, however, that RA action could be diversified to other cellular signaling pathways, the so-called nongenomic action of RA. For example, RA has been shown to modulate PKC activity by binding directly to PKC. RA binds directly to the C2-domain of PKC␣ (Ochoa et al., 2002), as determined by structural analysis of the cocrystalized C2-domain of PKC with RA. In addition, RA binding to the phosphatidyl serine binding site of PKC␣ was determined by photoaffinity labeling assay (Radominska-P...

Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine KRAS/p53-mutant lung adenocarcinoma cell line with high metastatic potential and an orthotopic syngeneic mouse model and in vitro using a CXCR2 small molecule antagonist (SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis and RAS pathway activation. Expression of CXCL5 was regulated by promoter methylation. The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.