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Gene Review

TMEFF2  -  transmembrane protein with EGF-like and...

Homo sapiens

Synonyms: CT120.2, HPP1, Hyperplastic polyposis protein 1, TENB2, TPEF, ...
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Disease relevance of TMEFF2


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


Biological context of TMEFF2


Anatomical context of TMEFF2


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].


  1. Repression of the TMEFF2 promoter by c-Myc. Gery, S., Koeffler, H.P. J. Mol. Biol. (2003) [Pubmed]
  2. HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Young, J., Biden, K.G., Simms, L.A., Huggard, P., Karamatic, R., Eyre, H.J., Sutherland, G.R., Herath, N., Barker, M., Anderson, G.J., Fitzpatrick, D.R., Ramm, G.A., Jass, J.R., Leggett, B.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Aberrant methylation of the HPP1 gene in ulcerative colitis-associated colorectal carcinoma. Sato, F., Shibata, D., Harpaz, N., Xu, Y., Yin, J., Mori, Y., Wang, S., Olaru, A., Deacu, E., Selaru, F.M., Kimos, M.C., Hytiroglou, P., Young, J., Leggett, B., Gazdar, A.F., Toyooka, S., Abraham, J.M., Meltzer, S.J. Cancer Res. (2002) [Pubmed]
  4. Transient vs. prolonged histone hyperacetylation: effects on colon cancer cell growth, differentiation, and apoptosis. Wu, J.T., Archer, S.Y., Hinnebusch, B., Meng, S., Hodin, R.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  5. Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Chow, E., Lipton, L., Lynch, E., D'Souza, R., Aragona, C., Hodgkin, L., Brown, G., Winship, I., Barker, M., Buchanan, D., Cowie, S., Nasioulas, S., du Sart, D., Young, J., Leggett, B., Jass, J., Macrae, F. Gastroenterology (2006) [Pubmed]
  6. Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability. Schulmann, K., Mori, Y., Croog, V., Yin, J., Olaru, A., Sterian, A., Sato, F., Wang, S., Xu, Y., Deacu, E., Berki, A.T., Hamilton, J.P., Kan, T., Abraham, J.M., Schmiegel, W., Harpaz, N., Meltzer, S.J. Gastroenterology (2005) [Pubmed]
  7. Phenotypic and molecular characteristics of hyperplastic polyposis. Rashid, A., Houlihan, P.S., Booker, S., Petersen, G.M., Giardiello, F.M., Hamilton, S.R. Gastroenterology (2000) [Pubmed]
  8. TENB2, a proteoglycan identified in prostate cancer that is associated with disease progression and androgen independence. Glynne-Jones, E., Harper, M.E., Seery, L.T., James, R., Anglin, I., Morgan, H.E., Taylor, K.M., Gee, J.M., Nicholson, R.I. Int. J. Cancer (2001) [Pubmed]
  9. A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells. Uchida, T., Wada, K., Akamatsu, T., Yonezawa, M., Noguchi, H., Mizoguchi, A., Kasuga, M., Sakamoto, C. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  10. Targeting tomoregulin for radioimmunotherapy of prostate cancer. Zhao, X.Y., Schneider, D., Biroc, S.L., Parry, R., Alicke, B., Toy, P., Xuan, J.A., Sakamoto, C., Wada, K., Schulze, M., Müller-Tiemann, B., Parry, G., Dinter, H. Cancer Res. (2005) [Pubmed]
  11. Expression of thyroid receptor isoforms in the human fetal central nervous system and the effects of intrauterine growth restriction. Kilby, M.D., Gittoes, N., McCabe, C., Verhaeg, J., Franklyn, J.A. Clin. Endocrinol. (Oxf) (2000) [Pubmed]
  12. Morphologic changes, mucin secretion, carcinoembryonic antigen (CEA) and peanut lectin reactivity in colonic mucosa of patients at high risk for colorectal cancer. Altavilla, G., Lanza, G., Rossi, S., Cavazzini, L. Tumori. (1984) [Pubmed]
  13. A truncated isoform of TMEFF2 encodes a secreted protein in prostate cancer cells. Quayle, S.N., Sadar, M.D. Genomics (2006) [Pubmed]
  14. The gene for a novel transmembrane protein containing epidermal growth factor and follistatin domains is frequently hypermethylated in human tumor cells. Liang, G., Robertson, K.D., Talmadge, C., Sumegi, J., Jones, P.A. Cancer Res. (2000) [Pubmed]
  15. Identification and characterization of TMEFF2, a novel survival factor for hippocampal and mesencephalic neurons. Horie, M., Mitsumoto, Y., Kyushiki, H., Kanemoto, N., Watanabe, A., Taniguchi, Y., Nishino, N., Okamoto, T., Kondo, M., Mori, T., Noguchi, K., Nakamura, Y., Takahashi, E., Tanigami, A. Genomics (2000) [Pubmed]
  16. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Schulmann, K., Sterian, A., Berki, A., Yin, J., Sato, F., Xu, Y., Olaru, A., Wang, S., Mori, Y., Deacu, E., Hamilton, J., Kan, T., Krasna, M.J., Beer, D.G., Pepe, M.S., Abraham, J.M., Feng, Z., Schmiegel, W., Greenwald, B.D., Meltzer, S.J. Oncogene (2005) [Pubmed]
  17. TMEFF2 is an androgen-regulated gene exhibiting antiproliferative effects in prostate cancer cells. Gery, S., Sawyers, C.L., Agus, D.B., Said, J.W., Koeffler, H.P. Oncogene (2002) [Pubmed]
  18. BRAF mutations in aberrant crypt foci and hyperplastic polyposis. Beach, R., Chan, A.O., Wu, T.T., White, J.A., Morris, J.S., Lunagomez, S., Broaddus, R.R., Issa, J.P., Hamilton, S.R., Rashid, A. Am. J. Pathol. (2005) [Pubmed]
  19. Mutation searching in colorectal cancer studies: experience with a denaturing high-pressure liquid chromatography system for exon-by-exon scanning of tumour suppressor genes. Young, J., Barker, M., Fraser, L., Walsh, M.D., Spring, K., Biden, K.G., Hopper, J.L., Leggett, B.A., Jass, J.R. Pathology. (2002) [Pubmed]
  20. Methylation of serum DNA is an independent prognostic marker in colorectal cancer. Wallner, M., Herbst, A., Behrens, A., Crispin, A., Stieber, P., G??ke, B., Lamerz, R., Kolligs, F.T. Clin. Cancer Res. (2006) [Pubmed]
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