Disease relevance of TMEFF2

• Recently, we showed that expression of TMEFF2 could inhibit prostate cancer cell growth [1].
• Using reverse transcription-PCR, HPP1 was expressed in 28 of 30 (93%) normal colonic samples but in only seven of 30 (23%) colorectal cancers (P < 0.001) [2].
• HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers [2].
• HPP1 methylation was observed in 24 of 48 (50%) adenocarcinomas and in 4 of 10 (40%) dysplasias [3].
• HPP1 expression in the HCT116 colon cancer cell line was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine [3].

Psychiatry related information on TMEFF2

• Histone hyperacetylation, assessed by acid-urea-triton gel electrophoresis, was transient in the T group but persisted for up to 24 h in the butyrate and TR groups [4].

High impact information on TMEFF2

• The patients were analyzed for age at first diagnosis, features of hyperplastic polyposis, family histories of polyposis and colorectal cancer (CRC), coexisting adenomas, serrated adenomas, incidence of CRC, and microsatellite instability in the tumours [5].
• Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias [6].
• HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively [6].
• Hyperplastic polyposis was associated with a family history of colorectal cancer (P = 0.01) and with loss of chromosome 1p in HP (21% vs. 0%, P = 0.001) [7].
• METHODS: We evaluated clinical-pathological and molecular characteristics of 129 HPs, 6 serrated adenomas, and 3 admixed hyperplastic-adenomatous polyps from 13 patients with hyperplastic polyposis (more than 20 HPs), 5 patients with a large HP (>/=1 cm in diameter), and 5 patients with multiple HPs (5-10 HPs) [7].

Chemical compound and disease context of TMEFF2

• TENB2, a proteoglycan identified in prostate cancer that is associated with disease progression and androgen independence [8].
• Soluble TR stimulated erbB-4 tyrosine phosphorylation in MKN 28 gastric cancer cells, although it was weak compared to neuregulin-induced erbB-4 tyrosine phosphorylation; this suggests that TR might be a ligand for erbB-4- or erbB-4-related receptor tyrosine kinase [9].
• Immunohistochemical studies of tomoregulin protein in clinical samples show its location in the luminal epithelium of normal prostate, benign prostatic hyperplasia, and prostatic intraepithelial neoplasia [10].
• Our finding that in severe IUGR the expression of TR isoforms in the human fetal cerebral cortex and cerebellum was significantly reduced, in association with reduced circulating thyroid hormone concentrations indicate that changes in free ligand and receptors may affect CNS development [11].
• In high risk patients (Groups A and B) the most relevant modifications were dysplasia with hyposecretion and hyperplasia with sialomucin secretion (TR-type change); in Group A 31 adenomas and 19 hyperplastic polyps also were found [12].

Biological context of TMEFF2

• In addition, the TMEFF2 gene is frequently hypermethylated in human tumor cells, suggesting that it might be a tumor suppressor gene [1].
• The 0.7 kb region upstream to the TMEFF2 transcription start site encompasses the minimal promoter required for TMEFF2 expression [1].
• This variant encodes an isoform of TMEFF2 that is truncated after the first four coding exons, eliminating both the EGF-like and the transmembrane domains [13].
• Silencing of HPP1 by methylation may increase the probability of neoplastic transformation [2].
• TPEF maps to human chromosome 2q33, where frequent loss of heterozygosity is seen in various human tumors, and TPEF was not expressed in most human colon and various other tumor cell lines examined by reverse transcription-PCR [14].

Anatomical context of TMEFF2

• TMEFF2 increased survival of neurons from the hippocampus and midbrain, but not from the cerebral cortex, indicating that the survival effects of TMEFF2 are specific to certain cell types [15].
• In situ hybridization analysis revealed that TMEFF2 is widely expressed in the brain, including hippocampal cornu ammonis, dentate gyrus, and substantia nigra pars compacta [15].
• Rapid amplification of cDNA ends was used to isolate HPP1 from normal mucosa [2].
• There was an inverse relationship between methylation level and mRNA expression in cancers (r = -0.67; P < 0.001), and 5-aza-2-deoxycytidine treatment restored HPP1 expression in two colorectal cancer cell lines [2].
• TR may have important roles in normal development of middle to late stages of embryos and maintenance of adult central nervous system tissues as high expression of TR mRNAs was observed in these tissues [9].

Associations of TMEFF2 with chemical compounds

• To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2'-deoxycytidine (Aza-C) treatment [16].
• The 5' region of HPP1 included a CpG island containing 49 CpG sites, of which 96% were found to be methylated by bisulfite sequencing of DNA from colonic tumor samples [2].
• Northern analysis and competitive PCR were used to demonstrate significantly increased TENB2 expression (p = 0.0003) on the acquisition of androgen independence in the model system [8].
• Studies of recombinant protein expression demonstrate that TENB2 is a chondroitin sulphate proteoglycan [8].
• Expression of the gene was controlled by androgen as shown by dihydrotestosterone markedly increasing TMEFF2 expression in LNCaP cells [17].

Other interactions of TMEFF2

• Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk [16].
• METHODS: A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1 , HPP1 , and RAB-32 . Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs [6].
• BRAF mutations in aberrant crypt foci and hyperplastic polyposis [18].
• The highest rate was found in HPP1, where all hits were found to be sequence variants, and the lowest rate was found in MSH2, where manual sequencing failed to find a sequence variant in 17% of the hits attained [19].
• Moreover, methylation of HPP1/TPEF was also associated with serum carcinoembryonic antigen [20].

Analytical, diagnostic and therapeutic context of TMEFF2

• An inverse correlation between TMEFF2 and c-Myc expression was found in CWR22 prostate xenografts [1].
• Real-time RT-PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA [16].
• Quantitative methylation-specific PCR and quantitative reverse transcription-PCR were used to determine HPP1 gene methylation and expression levels, respectively [3].
• Sequence analysis revealed novel cDNA clones, the protein products of which were designated tomoregulin (TR) and consisted of at least three isoforms which were distinguished by their cytoplasmic domains [9].
• Also, androgen-dependent human prostate cancer xenografts (CWR22) expressed high levels of TMEFF2 and these levels markedly decreased by day 10 after castration of the mice [17].

References