In recent years considerable advances have been made in our knowledge of the peptide moiety of human mucins through cDNA cloning. In many diseases disorders in mucin biosynthesis are observed, which result either from changes in the synthesis of the carbohydrate side chains or from differences in the relative expression of the different apomucins, each of which may affect physical properties of the viscous gel. We describe in situ hybridization studies on healthy human mucosae with five different oligonucleotide probes corresponding to each of the human genes known to date that encode secreted mucins, i.e., MUC 2, 3, 4 (HGM nomenclature) and 5B, 5C (proposed name). These genes present a nucleic tandem repeat organization. The choice of oligonucleotide probes was made to amplify the signal by hybridization of many small probes on the same mRNA molecules. A characteristic pattern of mucin gene expression was observed for each mucosa.
The 11p15 mucin genes (MUC2, MUC5AC, MUC5B and MUC6) possess a cell-specific pattern of expression in normal lung that is altered during carcinogenesis. Growth factors of the epidermal growth factor family are known to target key genes that in turn may affect the homeostasis of lung mucosae. Our aim was to study the regulation of the 11p15 mucin genes both at the promoter and protein levels to assess whether their altered expression may represent a key event during lung carcinogenesis. Studies were performed in the mucoepidermoid NCI-H292 lung cancer cell line. Cell treatment with epidermal growth factor (EGF), transforming growth factor ␣ (TGF-␣), or tumor necrosis factor ␣ (TNF-␣) resulted in a dramatic increase of MUC2 and MUC5AC mRNAs levels, promoter activity, and apomucin expression, whereas those of MUC5B and MUC6 were unchanged. pGL3 deletion mutants of MUC2, MUC5AC, and MUC5B promoters were constructed and used in transient transfection assays to characterize EGF-and TGF-␣-responsive regulatory regions within the promoters. They were located in the ؊2627/؊2097 and ؊202/؊1 regions of MUC2 and MUC5AC promoters, respectively. Finally, we demonstrate that transcription factor Sp1 not only binds and activates MUC2 and MUC5AC promoters but also participates to their EGF-and TGF-␣-mediated up-regulation. We also show that Sp3 is a strong inhibitor of 11p15 mucin gene transcription. In conclusion, MUC2 and MUC5AC are two target genes of EGFR ligands in lung cancer cells, and up-regulation of these two genes goes through concomitant activation of the EGFR/Ras/Raf/Extracellular Signal-regulated Kinase-signaling pathway and Sp1 binding to their promoters.Mucins have been postulated to be important molecules in maintaining epithelium homeostasis in inflammatory diseases and cancer in that they are large O-glycoproteins expressed either at the cell surface or as secreted molecules to form a protective gel. Mucin genes MUC2, MUC5AC, MUC5B, and MUC6 are clustered on the p15 arm of chromosome 11 (1) and encode large secreted O-glycoproteins that participate in mucus formation and epithelium protection (2, 3). However, their precise biological role as key genes during sequential steps of lung carcinogenesis has yet to be proven.In the surface epithelium of the respiratory tract, MUC5AC is exclusively expressed in mucus-secreting goblet cells, whereas MUC1 and MUC4 are expressed in all epithelial cells. MUC5B is prominent in the mucous cells of the submucosal glands, and MUC2 is weakly expressed in both cell types (4 -6). In epithelial lung diseases this pattern of expression is altered and has been correlated to poor prognosis of the tumor (invasiveness, metastasis) (7). For example, aberrant expression of MUC6 in bronchiopulmonary adenocarcinoma, loss of expression of MUC5AC and MUC5B in epidermoid carcinoma, and a strong expression of the four 11p15 mucin genes in bronchioalveolar carcinoma was recently described (5).Growth factors are thought to be involved in goblet cell production because hypersecretory diseases ar...
As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
Purpose: Malignant mesothelioma is a highly aggressive tumor and is often diagnosed too late for a curative treatment.We compared diagnostic and prognostic values of mesothelin and osteopontin in172 patients suspected of malignant pleural mesothelioma (MPM) and in a control group of 112 asymptomatic asbestos-exposed subjects. Experimental Design: Osteopontin and mesothelin were assayed with commercial ELISA kits in a series of 43 patients with pleural metastases of various carcinomas, 33 patients with benign pleural lesions associated with asbestos exposure, 96 patients with MPMs, and 112 asbestosexposed healthy subjects. Results were correlated with patient's diagnosis and survival. Results: Serum osteopontin level was higher in MPM patients compared with healthy asbestosexposed subjects and had a good capability to distinguish between these two populations. However, osteopontin was unable to distinguish between MPM and pleural metastatic carcinoma or benign pleural lesions associated with asbestos exposure. Neither plasma nor pleural fluid osteopontin were more powerful in this respect. Serum mesothelin had a good ability for diagnosing MPM but was unable to identify patients with nonepithelioid mesothelioma subtypes. Survival analysis identified tumor histologic subtype along with serum osteopontin and serum mesothelin as independent prognostic factors in mesothelioma patients. Conclusions: Osteopontin has a lower diagnostic accuracy than mesothelin in patients suspected of MPM. Insufficient specificity limits osteopontin utility as diagnostic marker. Both molecules have a potential value as prognostic markers.
In patients with chronic diffuse infiltrative lung disease, areas of ground-glass attenuation not associated with traction bronchiectasis or bronchiolectasis are a reliable indicator of inflammation.
We show that SMRPs may be a promising marker for mesothelioma diagnosis when measured either in serum or pleural fluid. The diagnostic value of SMRPs was similar in both types of samples, but pleural fluid SMRPs may better discriminate mesothelioma from pleural metastasis.
Malignant pleural mesothelioma (MPM) is recognized as heterogeneous based both on histology and molecular profiling. Histology addresses inter-tumor and intra-tumor heterogeneity in MPM and describes three major types: epithelioid, sarcomatoid and biphasic, a combination of the former two types. Molecular profiling studies have not addressed intra-tumor heterogeneity in MPM to date. Here, we use a deconvolution approach and show that molecular gradients shed new light on the intra-tumor heterogeneity of MPM, leading to a reconsideration of MPM molecular classifications. We show that each tumor can be decomposed as a combination of epithelioid-like and sarcomatoid-like components whose proportions are highly associated with the prognosis. Moreover, we show that this more subtle way of characterizing MPM heterogeneity provides a better understanding of the underlying oncogenic pathways and the related epigenetic regulation and immune and stromal contexts. We discuss the implications of these findings for guiding therapeutic strategies, particularly immunotherapies and targeted therapies.
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