No abstract

BACKGROUND Despite increasingly radical surgery for esophageal carcinoma, a large number of patients still experience recurrent disease soon after operation. The current study was undertaken to evaluate the pattern of recurrence after curative esophagectomy for cancer of the thoracic esophagus and to identify factors predictive of recurrent disease. METHODS A total of 439 consecutive patients discharged from the authors' institution following R0 resection between January 1982 and July 2002 were followed for evidence of recurrence over a mean interval of 37.3 (range, 1–207) months. RESULTS Overall 1‐, 3‐ and 5‐years survival rates were 91%, 54%, and 41%, respectively. Some 230 patients (52.4%) developed proven recurrence, of whom 24 were alive and 206 were dead at the time of writing. The median time to recurrence was 12.0 (range, 6–96) months, with a median survival thereafter of 7.0 (range, 0–83) months. The pattern of recurrence was local in 12.1%, regional in 20.5% (cervical 3.6%, mediastinal 14.8%, and abdominal 2.1%), and distant in 19.8%, respectively. The overall pattern of dissemination was significantly different according to the histologic subtype (P = 0.021). One hundred five (45.7%) of all recurrences occurred within 12 months of surgery, with local, regional, and distant recurrence occurring at a median of 14.0 (range, 6–77), 13.5 (range, 6–73), and 11.0 (range, 6–96) months, respectively; A factor predictive of recurrent disease was histologic tumor depth invasion (P = 0.001). CONCLUSIONS Depth of tumor invasion should be used to identify patients who will have recurrence within 12 months of operation, so that these patients may be either entered into trials of multimodality treatment or offered nonsurgical palliation. Cancer 2003;97:1616–23. © 2003 American Cancer Society. DOI 10.1002/cncr.11228

SCFAs (short-chain fatty acids), fermentation products of bacteria, influence epithelial-specific gene expression. We hypothesize that SCFAs affect goblet-cell-specific mucin MUC2 expression and thereby alter epithelial protection. In the present study, our aim was to investigate the mechanisms that regulate butyrate-mediated effects on MUC2 synthesis. Human goblet cell-like LS174T cells were treated with SCFAs, after which MUC2 mRNA levels and stability, and MUC2 protein expression were analysed. SCFA-responsive regions and cis-elements within the MUC2 promoter were identified by transfection and gel-shift assays. The effects of butyrate on histone H3/H4 status at the MUC2 promoter were established by chromatin immunoprecipitation. Butyrate (at 1 mM), as well as propionate, induced an increase in MUC2 mRNA levels. MUC2 mRNA levels returned to basal levels after incubation with 5-15 mM butyrate. Interestingly, this decrease was not due to loss of RNA stability. In contrast, at concentrations of 5-15 mM propionate, MUC2 mRNA levels remained increased. Promoter-regulation studies revealed an active butyrate-responsive region at -947/-371 within the MUC2 promoter. In this region we identified an active AP1 (c-Fos/c-Jun) cis-element at -818/-808 that mediates butyrate-induced activation of the promoter. Finally, MUC2 regulation by butyrate at 10-15 mM was associated with increased acetylation of histone H3 and H4 and methylation of H3 at the MUC2 promoter. In conclusion, 1 mM butyrate and 1-15 mM propionate increase MUC2 expression. The effects of butyrate on MUC2 mRNA are mediated via AP-1 and acetylation/methylation of histones at the MUC2 promoter.

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...