Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test. GPX2 and TXNRD3 showed a higher expression and GPX3, SELENOP, SELENOS, and SEPHS2 exhibited a lower expression in the disease tissue from adenomas and both cancer groups (p-values from 0.023 to <0.001). In the Czech cohort, up-regulation of GPX1, SELENOH, and SOD2 and down-regulation of SELENBP1, SELENON, and SELENOK (p-values 0.036 to <0.001) was also observed. We further examined the correlation of gene expression with serum Se status (assessed by Se and selenoprotein P, SELENOP) in the Irish patients. While there were no significant correlations with both Se status markers, SELENOF, SELENOK, and TXNRD1 tumor tissue expression positively correlated with Se, while TXNRD2 and TXNRD3 negatively correlated with SELENOP. In an analysis restricted to the larger Czech CRC patient cohort, Cox regression showed no major association of transcript levels with patient survival, except for an association of higher SELENOF gene expression with both a lower disease-free and overall survival. Several selenoproteins were differentially expressed in the disease tissue compared to the normal tissue of both CRA and CRC patients. Altered selenoprotein expression may serve as a marker of functional Se status and colorectal adenoma to cancer progression.

Biomedical Centre Medical and Teaching School Pilsen Charles University Prague 323 00 Pilsen Czech Republic

Cancer Biology and Therapeutics Group UCD Conway Institute University College Dublin D04 V1W8 Dublin Ireland

Department of Pathology and Laboratory Medicine St Vincent's University Hospital D04 T6F4 Dublin Ireland

Institute for Experimental Endocrinology University Medical School Berlin D 13353 Berlin Germany

Teaching Hospital and Medical School Charles University Prague 306 05 Pilsen Czech Republic

Zobrazit více v PubMed

Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in globocan 2012. Int. J. Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210. PubMed DOI

Cappellani A., Zanghi A., Di Vita M., Cavallaro A., Piccolo G., Veroux P., Lo Menzo E., Cavallaro V., de Paoli P., Veroux M., et al. Strong correlation between diet and development of colorectal cancer. Front. Biosci. 2013;18:190–198. PubMed

Labunskyy V.M., Hatfield D.L., Gladyshev V.N. Selenoproteins: Molecular pathways and physiological roles. Physiol. Rev. 2014;94:739–777. doi: 10.1152/physrev.00039.2013. PubMed DOI PMC

Hatfield D.L., Tsuji P.A., Carlson B.A., Gladyshev V.N. Selenium and selenocysteine: Roles in cancer, health, and development. Trends Biochem. Sci. 2014;39:112–120. doi: 10.1016/j.tibs.2013.12.007. PubMed DOI PMC

Steinbrenner H., Speckmann B., Klotz L.O. Selenoproteins: Antioxidant selenoenzymes and beyond. Arch. Biochem. Biophys. 2016;595:113–119. doi: 10.1016/j.abb.2015.06.024. PubMed DOI

Meplan C. Selenium and chronic diseases: A nutritional genomics perspective. Nutrients. 2015;7:3621–3651. doi: 10.3390/nu7053621. PubMed DOI PMC

Hughes D.J., Fedirko V., Jenab M., Schomburg L., Meplan C., Freisling H., Bueno-de-Mesquita H.B., Hybsier S., Becker N.P., Czuban M., et al. Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort. Int. J. Cancer. 2015;136:1149–1161. doi: 10.1002/ijc.29071. PubMed DOI

Meplan C., Hesketh J. Selenium and cancer: A story that should not be forgotten-insights from genomics. Adv. Nutr. Cancer. 2014;159:145–166. PubMed

Meplan C., Johnson I.T., Polley A.C., Cockell S., Bradburn D.M., Commane D.M., Arasaradnam R.P., Mulholland F., Zupanic A., Mathers J.C., et al. Transcriptomics and proteomics show that selenium affects inflammation, cytoskeleton, and cancer pathways in human rectal biopsies. FASEB J. 2016;30:2812–2825. doi: 10.1096/fj.201600251R. PubMed DOI

Peters K.M., Carlson B.A., Gladyshev V.N., Tsuji P.A. Selenoproteins in colon cancer. Free Radic. Biol. Med. 2018 doi: 10.1016/j.freeradbiomed.2018.05.075. PubMed DOI PMC

Schomburg L., Schweizer U. Hierarchical regulation of selenoprotein expression and sex-specific effects of selenium. Biochim. Biophys. Acta. 2009;1790:1453–1462. doi: 10.1016/j.bbagen.2009.03.015. PubMed DOI

Bertz M., Kuhn K., Koeberle S.C., Muller M.F., Hoelzer D., Thies K., Deubel S., Thierbach R., Kipp A.P. Selenoprotein H controls cell cycle progression and proliferation of human colorectal cancer cells. Free Radic. Biol. Med. 2018 doi: 10.1016/j.freeradbiomed.2018.01.010. PubMed DOI

Al-Taie O.H., Uceyler N., Eubner U., Jakob F., Mork H., Scheurlen M., Brigelius-Flohe R., Schottker K., Abel J., Thalheimer A., et al. Expression profiling and genetic alterations of the selenoproteins GI-GPx and SePP in colorectal carcinogenesis. Nutr. Cancer. 2004;48:6–14. doi: 10.1207/s15327914nc4801_2. PubMed DOI

Yagublu V., Arthur J.R., Babayeva S.N., Nicol F., Post S., Keese M. Expression of selenium-containing proteins in human colon carcinoma tissue. Anticancer Res. 2011;31:2693–2698. PubMed

Murawaki Y., Tsuchiya H., Kanbe T., Harada K., Yashima K., Nozaka K., Tanida O., Kohno M., Mukoyama T., Nishimuki E., et al. Aberrant expression of selenoproteins in the progression of colorectal cancer. Cancer Lett. 2008;259:218–230. doi: 10.1016/j.canlet.2007.10.019. PubMed DOI

Meplan C., Hughes D.J., Pardini B., Naccarati A., Soucek P., Vodickova L., Hlavata I., Vrana D., Vodicka P., Hesketh J.E. Genetic variants in selenoprotein genes increase risk of colorectal cancer. Carcinogenesis. 2010;31:1074–1079. doi: 10.1093/carcin/bgq076. PubMed DOI

Reszka E., Jablonska E., Gromadzinska J., Wasowicz W. Relevance of selenoprotein transcripts for selenium status in humans. Genes Nutr. 2012;7:127–137. doi: 10.1007/s12263-011-0246-6. PubMed DOI PMC

Flanagan L., Schmid J., Ebert M., Soucek P., Kunicka T., Liska V., Bruha J., Neary P., Dezeeuw N., Tommasino M., et al. Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. Eur. J. Clin. Microbiol. Infect. Dis. 2014;33:1381–1390. doi: 10.1007/s10096-014-2081-3. PubMed DOI

Winawer S.J., Zauber A.G. The advanced adenoma as the primary target of screening. Gastrointest. Endosc. Clin. N. Am. 2002;12:1–9. doi: 10.1016/S1052-5157(03)00053-9. PubMed DOI

Hlavata I., Mohelnikova-Duchonova B., Vaclavikova R., Liska V., Pitule P., Novak P., Bruha J., Vycital O., Holubec L., Treska V., et al. The role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis. 2012;27:187–196. doi: 10.1093/mutage/ger075. PubMed DOI

Brynychova V., Hlavac V., Ehrlichova M., Vaclavikova R., Pecha V., Trnkova M., Wald M., Mrhalova M., Kubackova K., Pikus T., et al. Importance of transcript levels of caspase-2 isoforms s and l for breast carcinoma progression. Future Oncol. 2013;9:427–438. doi: 10.2217/fon.12.200. PubMed DOI

Soucek P., Anzenbacher P., Skoumalova I., Dvorak M. Expression of cytochrome p450 genes in CD34+ hematopoietic stem and progenitor cells. Stem Cells. 2005;23:1417–1422. doi: 10.1634/stemcells.2005-0066. PubMed DOI

Bustin S.A. Why the need for qPCR publication guidelines?—The case for MIQE. Methods. 2010;50:217–226. doi: 10.1016/j.ymeth.2009.12.006. PubMed DOI

Hughes D.J., Duarte-Salles T., Hybsier S., Trichopoulou A., Stepien M., Aleksandrova K., Overvad K., Tjonneland A., Olsen A., Affret A., et al. Prediagnostic selenium status and hepatobiliary cancer risk in the European prospective investigation into cancer and nutrition cohort. Am. J. Clin. Nutr. 2016;104:406–414. doi: 10.3945/ajcn.116.131672. PubMed DOI PMC

Meplan C., Hesketh J. The influence of selenium and selenoprotein gene variants on colorectal cancer risk. Mutagenesis. 2012;27:177–186. doi: 10.1093/mutage/ger058. PubMed DOI

Kipp A., Banning A., van Schothorst E.M., Meplan C., Schomburg L., Evelo C., Coort S., Gaj S., Keijer J., Hesketh J., et al. Four selenoproteins, protein biosynthesis, and Wnt signalling are particularly sensitive to limited selenium intake in mouse colon. Molecular Nutr. Food Res. 2009;53:1561–1572. doi: 10.1002/mnfr.200900105. PubMed DOI

Speckmann B., Steinbrenner H. Selenium and selenoproteins in inflammatory bowel diseases and experimental colitis. Inflamm. Bowel Dis. 2014;20:1110–1119. doi: 10.1097/MIB.0000000000000020. PubMed DOI

Hesketh J., Meplan C. Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: Focus on selenium as an exemplar. Proc. Nutr. Soc. 2011;3:1–9. doi: 10.1017/S0029665111000115. PubMed DOI

Ren B., Liu M., Ni J., Tian J. Role of selenoprotein F in protein folding and secretion: Potential involvement in human disease. Nutrients. 2018;10:1619. doi: 10.3390/nu10111619. PubMed DOI PMC

Irons R., Tsuji P.A., Carlson B.A., Ouyang P., Yoo M.H., Xu X.M., Hatfield D.L., Gladyshev V.N., Davis C.D. Deficiency in the 15-kDa selenoprotein inhibits tumorigenicity and metastasis of colon cancer cells. Cancer Prev. Res. 2010;3:630–639. doi: 10.1158/1940-6207.CAPR-10-0003. PubMed DOI PMC

Tsuji P.A., Carlson B.A., Naranjo-Suarez S., Yoo M.H., Xu X.M., Fomenko D.E., Gladyshev V.N., Hatfield D.L., Davis C.D. Knockout of the 15 kDa selenoprotein protects against chemically-induced aberrant crypt formation in mice. PLoS ONE. 2012;7:e50574. doi: 10.1371/journal.pone.0050574. PubMed DOI PMC

Mork H., Al-Taie O.H., Bahr K., Zierer A., Beck C., Scheurlen M., Jakob F., Kohrle J. Inverse mRNA expression of the selenocysteine-containing proteins GI-GPX and SePP in colorectal adenomas compared with adjacent normal mucosa. Nutr. Cancer. 2000;37:108–116. doi: 10.1207/S15327914NC3701_14. PubMed DOI

Novoselov S.V., Kryukov G.V., Xu X.M., Carlson B.A., Hatfield D.L., Gladyshev V.N. Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern. J. Biol. Chem. 2007;282:11960–11968. doi: 10.1074/jbc.M701605200. PubMed DOI

Wang N., Chen Y., Yang X., Jiang Y. Selenium-binding protein 1 is associated with the degree of colorectal cancer differentiation and is regulated by histone modification. Oncol. Rep. 2014;31:2506–2514. doi: 10.3892/or.2014.3141. PubMed DOI

Hughes D.J., Fedirko V., Jones J.S., Méplan C., Schomburg L., Hybsier S., Riboli E., Hesketh J., Jenab M. Association of selenoprotein and selenium pathway genetic variations with colorectal cancer risk and interaction with selenium status. In: Banuelos G.S., Lin Z.Q., Moraes M.F., Guilherme L.R.G., dos Reis A.R., editors. Global Advances in Selenium Research from Theory to Application. 1st ed. Taylor & Francis; London, UK: 2015. pp. 53–54.

Click B., Pinsky P.F., Hickey T., Doroudi M., Schoen R.E. Association of colonoscopy adenoma findings with long-term colorectal cancer incidence. JAMA. 2018;319:2021–2031. doi: 10.1001/jama.2018.5809. PubMed DOI PMC

Combs G.F., Jr. Biomarkers of selenium status. Nutrients. 2015;7:2209–2236. doi: 10.3390/nu7042209. PubMed DOI PMC

Johnson C.C., Fordyce F.M., Rayman M.P. Symposium on ‘Geographical and geological influences on nutrition’: Factors controlling the distribution of selenium in the environment and their impact on health and nutrition. Proc. Nutr. Soc. 2010;69:119–132. doi: 10.1017/S0029665109991807. PubMed DOI

The Associations of Selenoprotein Genetic Variants with the Risks of Colorectal Adenoma and Colorectal Cancer: Case-Control Studies in Irish and Czech Populations