Trefoil factor family 2 deficiency and immune response.

The protective effect of Trefoil Factor Family (TFF) proteins in the gastrointestinal tract by promoting the healing of injured mucosa is well known. An increasing body of evidence connects TFFs, especially, TFF2 and TFF3, with a possible role in immune regulation. TFF2 is able to inhibit lipopolysaccharide-induced nitric oxide production in monocytes and can potently limit leukocyte recruitment at the site of injury. An analysis of gene expression in gastrointestinal tissue of TFF2-deficient mice reveals some new aspects of TFF2's role in the immune response.

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer.

Our study aimed at elucidating which genetic alterations tend to form a network and could be applied as molecular markers of larynx squamous cell carcinoma (LSCC). A panel of genes involved in tumorigenesis was investigated. To search for the possible mechanisms of gene silencing, loss of heterozygosity (LOH) was analysed followed by testing DNA methylation and protein expression for those genes found with the highest frequency of LOH (CDKN2A (55.4%), MLH1 (46.0%), RB1 (35.7%)). A correlation of both LOH and hypermethylation with the loss of expression for CDKN2A and MLH1 was found. Disrupted Rb pathway (loss of expression of RB1 and/or of CDKN2A) in 55.9% of analysed cases confirmed the hypothesis that RB1 pathway is altered in head and neck squamous cell carcinomas, with CDKN2A (45%), rather than RB1 (11.8%) being more frequently inactivated. In LSCC, LOH tends to occur together in gene pairs or triplets. The pair MLH1/CDKN2A and triplets MLH1/TSG on 8p22/CDKN2A and MLH1/CDKN2A/RB1 are related to staging and grading. LOH in MLH1 correlates with lower and LOH in CDKN2A with higher grades of LSCC. It can be concluded that MLH1 and CDKN2A play an important role in LSCC development and progression.

Tumour necrosis factor alpha and nuclear factor kappaB inhibit transcription of human TFF3 encoding a gastrointestinal healing peptide.

BACKGROUND: and aims: Tumour necrosis factor alpha (TNF-alpha) induction of nuclear factor kappaB (NFkappaB) activation plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Trefoil factor family peptides TFF1, TFF2, and TFF3 exert protective, curative, and tumour suppressive functions in the gastrointestinal tract. In this study, we investigated effects of the TNF-alpha/NFkappaB regulatory pathway by TNF-alpha on expression of TFFs. METHODS: After TNF-alpha stimulation, expression of TFF genes was analysed by quantitative real time polymerase chain reaction and by reporter gene assays in the gastrointestinal tumour cell lines HT-29 and KATO III. Additionally, NFkappaB subunits and a constitutive repressive form of inhibitory factor kappaB (IkappaB) were transiently coexpressed. In vivo, morphological changes and expression of TFF3, mucins, and NFkappaB were monitored by immunohistochemistry in a rat model of 2,4,6-trinitrobenzene sulphonic acid induced colitis. RESULTS: TNF-alpha stimulation evoked up to 10-fold reduction of TFF3 expression in the colon tumour cell line HT-29. Downregulation of reporter gene transcription of TFF3 was observed with both TNF-alpha and NFkappaB, and was reversible by IkappaB. In vivo, the increase in epithelial expression of NFkappaB coincided with reduced TFF3 expression during the acute phase of experimental colitis. CONCLUSIONS: Downregulation of intestinal trefoil factor TFF3 is caused by repression of transcription through TNF-alpha and NFkappaB activation in vitro. In IBD, perpetual activation of NFkappaB activity may contribute to ulceration and decreased wound healing through reduced TFF3.

Variable distribution of TFF2 (Spasmolysin) alleles in Europeans does not indicate predisposition to gastric cancer.

Peptides belonging to the trefoil factor family (TFF) protect the gastrointestinal epithelia. Overexpression of TFFs was observed in pathological conditions such as gastritis, ulceration, metaplasia and neoplasia of the gastrointestinal tract. The aims of this work were to investigate the recently described TFF2 gene polymorphism in different European populations. DNA samples from blood of healthy individuals and gastric cancer patients were genotyped using the polymerase chain reaction. They were compared to a gastric cancer population. The results do not show any significant difference in allelic frequencies between gastric cancer patients and healthy individuals from Portugal. However, the frequency of the two alleles found varies considerably among Europeans.

A novel 25 bp tandem repeat within the human trefoil peptide gene TFF2 in 21q22.3: polymorphism and mammalian evolution.

Trefoil peptides belong to a family of small secretory proteins characterised by three intrachain disulfide bonds forming the trefoil motif (TFF-domain). They serve to maintain or repair the epithelial mucosa, and promote cell migration. They are predominantly found in gastrointestinal tissues, and are upregulated around areas of epithelial damage, and in meta- and neoplasia. The corresponding three genes are clustered in human 21q22.3. TFF2 is the only human one encoding two TFF-domains on separate exons. In between (intron 2), a novel 25 bp sequence is located that is tandemly repeated approximately 48 times, but is unique in the human genome. A diallelic polymorphism with a second allele comprising approximately 53 repeat units is present among individuals. Both alleles were cloned on BAC recombinants. In Caucasians (n = 78) the allele frequencies found are 0.85 and 0.15, respectively, representing a frequency of heterozygosity of 26%. Ape and monkey species exhibit homologous repeats of shorter total array length, whereas none is found in other mammals.