Cruciferous vegetables and colorectal cancer prevention through microRNA regulation: A review

References

• World Cancer Research Fund / American Institute for Cancer Research. (2007). Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: AICR.
   Google Scholar
• Abdull Razis, A. F., Bagatta, M., De Nicola, G. R., Iori, R. and Ioannides, C. (2010). Intact glucosinolates modulate hepatic cytochrome P450 and phase II conjugation activities and may contribute directly to the chemopreventive activity of cruciferous vegetables. Toxicology. 277:74–85.
   PubMed Web of Science ®Google Scholar
• Aggarwal, B. B. and Ichikawa, H. (2005). Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 4:1201–1215.
   PubMed Web of Science ®Google Scholar
• Antony, M. L., Kim, S. H. and Singh, S. V. (2012). Critical role of p53 upregulated modulator of apoptosis in benzyl isothiocyanate-induced apoptotic cell death. PLoS One. 7:e32267.
   PubMed Web of Science ®Google Scholar
• Appari, M., Babu, K. R., Kaczorowski, A., Gross, W. and Herr, I. (2014). Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition. Int. J. Oncol. 45:1391–1400.
   PubMed Web of Science ®Google Scholar
• Avila, F. W., Yang, Y., Faquin, V., Ramos, S. J., Guilherme, L. R., Thannhauser, T. W. and Li, L. (2014). Impact of selenium supply on Se-methylselenocysteine and glucosinolate accumulation in selenium-biofortified Brassica sprouts. Food Chem. 165:578–586.
   PubMed Web of Science ®Google Scholar
• Bakirtzi, K., Hatziapostolou, M., Karagiannides, I., Polytarchou, C., Jaeger, S., Iliopoulos, D. and Pothoulakis, C. (2011). Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors. Gastroenterology. 141:1749–1761, e1741.
   Web of Science ®Google Scholar
• Barillari, J., Iori, R., Rollin, P. and Hennion, F. (2005). Glucosinolates in the subantarctic crucifer Kerguelen cabbage (Pringlea antiscorbutica). J. Nat. Prod. 68:234–236.
   PubMed Web of Science ®Google Scholar
• Basu, A., Alder, H., Khiyami, A., Leahy, P., Croce, C. M. and Haldar, S. (2011). MicroRNA-375 and MicroRNA-221: Potential noncoding RNAs associated with antiproliferative activity of benzyl isothiocyanate in pancreatic cancer. Genes Cancer. 2:108–119.
   PubMedGoogle Scholar
• Bellinger, F. P., Raman, A. V., Reeves, M. A. and Berry, M. J. (2009). Regulation and function of selenoproteins in human disease. Biochem. J. 422:11–22.
   PubMed Web of Science ®Google Scholar
• Bonnesen, C., Eggleston, I. M. and Hayes, J. D. (2001). Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res. 61:6120–6130.
   PubMed Web of Science ®Google Scholar
• Bravo-Egana, V., Rosero, S., Molano, R. D., Pileggi, A., Ricordi, C., Dominguez-Bendala, J. and Pastori, R. L. (2008). Quantitative differential expression analysis reveals miR-7 as major islet microRNA. Biochem. Biophys. Res. Commun. 366:922–926.
   PubMed Web of Science ®Google Scholar
• Byun, S., Shin, S. H., Park, J., Lim, S., Lee, E., Lee, C., Sung, D., Farrand, L., Lee, S. R., Kim, K. H., Dong, Z., Lee, S. W. and Lee, K. W. (2016). Sulforaphene suppresses growth of colon cancer-derived tumors via induction of glutathione depletion and microtubule depolymerization. Mol. Nutr. Food Res. 60:1068–1078.
   PubMed Web of Science ®Google Scholar
• Castilla, M. A., Moreno-Bueno, G., Romero-Perez, L., Van De Vijver, K., Biscuola, M., Lopez-Garcia, M. A., Prat, J., Matias-Guiu, X., Cano, A., Oliva, E. and Palacios, J. (2011). Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J. Pathol. 223:72–80.
   PubMed Web of Science ®Google Scholar
• Cha, H. J., Lee, G. T., Lee, K. S., Lee, K. K., Hong, J. T., Lee, N. K., Kim, S. Y., Lee, B. M., An, I. S., Hahn, H. J., Ahn, K. J., Lee, S. J., An, S. and Bae, S. (2014). Photoprotective effect of arctiin against ultraviolet B-induced damage in HaCaT keratinocytes is mediated by microRNA expression changes. Mol. Med. Rep. 10:1363–1370.
   PubMed Web of Science ®Google Scholar
• Chen, X., Guo, X., Zhang, H., Xiang, Y., Chen, J., Yin, Y., Cai, X., Wang, K., Wang, G., Ba, Y., Zhu, L., Wang, J., Yang, R., Zhang, Y., Ren, Z., Zen, K., Zhang, J. and Zhang, C. Y. (2009). Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene. 28:1385–1392.
   PubMed Web of Science ®Google Scholar
• Chendrimada, T. P., Gregory, R. I., Kumaraswamy, E., Norman, J., Cooch, N., Nishikura, K. and Shiekhattar, R. (2005). TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 436:740–744.
   PubMed Web of Science ®Google Scholar
• Cheng, A. M., Byrom, M. W., Shelton, J. and Ford, L. P. (2005). Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 33:1290–1297.
   PubMed Web of Science ®Google Scholar
• Choi, H. J., Lim, D. Y. and Park, J. H. (2009). Induction of G1 and G2/M cell cycle arrests by the dietary compound 3,3′-diindolylmethane in HT-29 human colon cancer cells. BMC Gastroenterol. 9:39.
   PubMed Web of Science ®Google Scholar
• Chung, Y. K., Chi-Hung Or, R., Lu, C. H., Ouyang, W. T., Yang, S. Y. and Chang, C. C. (2015). Sulforaphane down-regulates SKP2 to stabilize p27(KIP1) for inducing antiproliferation in human colon adenocarcinoma cells. J. Biosci. Bioeng. 119:35–42.
   PubMed Web of Science ®Google Scholar
• Ciska, E., Martyniak-Przybyszewska, B. and Kozlowska, H. (2000). Content of glucosinolates in cruciferous vegetables grown at the same site for two years under different climatic conditions. J. Agric. Food Chem. 48:2862–2867.
   PubMed Web of Science ®Google Scholar
• Coates, E. M., Popa, G., Gill, C. I., McCann, M. J., McDougall, G. J., Stewart, D. and Rowland, I. (2007). Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer. J. Carcinog. 6:4.
   PubMedGoogle Scholar
• Crim, K. C., Sanders, L. M., Hong, M. Y., Taddeo, S. S., Turner, N. D., Chapkin, R. S. and Lupton, J. R. (2008). Upregulation of p21Waf1/Cip1 expression in vivo by butyrate administration can be chemoprotective or chemopromotive depending on the lipid component of the diet. Carcinogenesis. 29:1415–1420.
   PubMed Web of Science ®Google Scholar
• Cummings, J. H., Hill, M. J., Jenkins, D. J., Pearson, J. R. and Wiggins, H. S. (1976). Changes in fecal composition and colonic function due to cereal fiber. Am. J. Clin. Nutr. 29:1468–1473.
   PubMed Web of Science ®Google Scholar
• D'Antuono, L. F., Elementi, S. and Neri, R. (2008). Glucosinolates in Diplotaxis and Eruca leaves: Diversity, taxonomic relations and applied aspects. Phytochemistry. 69:187–199.
   PubMed Web of Science ®Google Scholar
• Dalmasso, G., Nguyen, H. T., Yan, Y., Laroui, H., Charania, M. A., Ayyadurai, S., Sitaraman, S. V. and Merlin, D. (2011). Microbiota modulate host gene expression via microRNAs. PLoS One. 6:e19293.
   PubMed Web of Science ®Google Scholar
• Danielsen, S. A., Eide, P. W., Nesbakken, A., Guren, T., Leithe, E. and Lothe, R. A. (2015). Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim. Biophys. Acta. 1855:104–121.
   PubMed Web of Science ®Google Scholar
• Davaatseren, M., Hwang, J. T., Park, J. H., Kim, M. S., Wang, S. and Sung, M. J. (2014). Allyl isothiocyanate ameliorates angiogenesis and inflammation in dextran sulfate sodium-induced acute colitis. PLoS One. 9:e102975.
   PubMed Web of Science ®Google Scholar
• Davidson, L. A., Wang, N., Shah, M. S., Lupton, J. R., Ivanov, I. and Chapkin, R. S. (2009). n-3 Polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis. 30:2077–2084.
   PubMed Web of Science ®Google Scholar
• de Vos, R. H. and Blijleven, W. G. (1988). The effect of processing conditions on glucosinolates in cruciferous vegetables. Z. Lebensm. Unters. Forsch. 187:525–529.
   PubMedGoogle Scholar
• Fahey, J. W., Zalcmann, A. T. and Talalay, P. (2001). The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry. 56:5–51.
   PubMed Web of Science ®Google Scholar
• Faraoni, I., Antonetti, F. R., Cardone, J. and Bonmassar, E. (2009). miR-155 gene: A typical multifunctional microRNA. Biochim. Biophys. Acta. 1792:497–505.
   PubMed Web of Science ®Google Scholar
• Farazi, T. A., Juranek, S. A. and Tuschl, T. (2008). The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members. Development. 135:1201–1214.
   PubMed Web of Science ®Google Scholar
• Felton, J. S. and Knize, M. G. (1991). Occurrence, identification, and bacterial mutagenicity of heterocyclic amines in cooked food. Mutat. Res. 259:205–217.
   PubMed Web of Science ®Google Scholar
• Fenwick, G. R. and Heaney, R. K. (1983). Glucosinolates and their breakdown products in cruciferous crops, foods and feedingstuffs. Food Chem. 11:249–271.
   Web of Science ®Google Scholar
• Ferguson, L. R. and Harris, P. J. (1996). Studies on the role of specific dietary fibres in protection against colorectal cancer. Mutat. Res. 350:173–184.
   PubMed Web of Science ®Google Scholar
• Ferrarini, L., Pellegrini, N., Mazzeo, T., Miglio, C., Galati, S., Milano, F., Rossi, C. and Buschini, A. (2012). Anti-proliferative activity and chemoprotective effects towards DNA oxidative damage of fresh and cooked Brassicaceae. Br. J. Nutr. 107:1324–1332.
   PubMed Web of Science ®Google Scholar
• Font, R., del Rio-Celestino, M., Cartea, E. and de Haro-Bailon, A. (2005). Quantification of glucosinolates in leaves of leaf rape (Brassica napus ssp. pabularia) by near-infrared spectroscopy. Phytochemistry. 66:175–185.
   PubMed Web of Science ®Google Scholar
• Forman, J. J., Legesse-Miller, A. and Coller, H. A. (2008). A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc. Natl. Acad. Sci. U. S. A. 105:14879–14884.
   PubMed Web of Science ®Google Scholar
• Frydoonfar, H. R., McGrath, D. R. and Spigelman, A. D. (2002). Inhibition of proliferation of a colon cancer cell line by indole-3-carbinol. Colorectal Dis. 4:205–207.
   PubMedGoogle Scholar
• Fukuda, T., Yamagata, K., Fujiyama, S., Matsumoto, T., Koshida, I., Yoshimura, K., Mihara, M., Naitou, M., Endoh, H., Nakamura, T., Akimoto, C., Yamamoto, Y., Katagiri, T., Foulds, C., Takezawa, S., Kitagawa, H., Takeyama, K., O'Malley, B. W. and Kato, S. (2007). DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nat. Cell Biol. 9:604–611.
   PubMed Web of Science ®Google Scholar
• Fukuda, Y., Kawasaki, H. and Taira, K. (2005). Exploration of human miRNA target genes in neuronal differentiation. Nucleic Acids Symp. Ser. (Oxf):341–342.
   PubMedGoogle Scholar
• Graser, G., Schneider, B., Oldham, N. J. and Gershenzon, J. (2000). The methionine chain elongation pathway in the biosynthesis of glucosinolates in Eruca sativa (Brassicaceae). Arch. Biochem. Biophys. 378:411–419.
   PubMed Web of Science ®Google Scholar
• Gregory, R. I., Chendrimada, T. P., Cooch, N. and Shiekhattar, R. (2005). Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 123:631–640.
   PubMed Web of Science ®Google Scholar
• Hahn, C., Muller, A., Kuhnert, N. and Albach, D. (2016). Diversity of Kale (Brassica oleracea var. sabellica): Glucosinolate content and phylogenetic relationships. J. Agric. Food Chem. 64:3215–3225.
   PubMed Web of Science ®Google Scholar
• Han, J., Lee, Y., Yeom, K. H., Nam, J. W., Heo, I., Rhee, J. K., Sohn, S. Y., Cho, Y., Zhang, B. T. and Kim, V. N. (2006). Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell. 125:887–901.
   PubMed Web of Science ®Google Scholar
• Han, R., Sun, Q., Wu, J., Zheng, P. and Zhao, G. (2016). Sodium butyrate upregulates miR-203 expression to exert anti-proliferation effect on colorectal cancer cells. Cell. Physiol. Biochem. 39:1919–1929.
   PubMed Web of Science ®Google Scholar
• Hargraves, K. G., He, L. and Firestone, G. L. (2016). Phytochemical regulation of the tumor suppressive microRNA, miR-34a, by p53-dependent and independent responses in human breast cancer cells. Mol. Carcinog. 55:486–498.
   PubMed Web of Science ®Google Scholar
• He, H., Liu, L., Song, S., Tang, X. and Wang, Y. (2003). Evaluation of glucosinolate composition and contents in chinese brassica vegetablesed. Acta. Hortic. 620:85–92.
   Google Scholar
• He, L., He, X., Lim, L. P., de Stanchina, E., Xuan, Z., Liang, Y., Xue, W., Zender, L., Magnus, J., Ridzon, D., Jackson, A. L., Linsley, P. S., Chen, C., Lowe, S. W., Cleary, M. A. and Hannon, G. J. (2007). A microRNA component of the p53 tumour suppressor network. Nature. 447:1130–1134.
   PubMed Web of Science ®Google Scholar
• Higdon, J. V., Delage, B., Williams, D. E. and Dashwood, R. H. (2007). Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis. Pharmacol. Res. 55:224–236.
   PubMed Web of Science ®Google Scholar
• Ho, E., Clarke, J. D. and Dashwood, R. H. (2009). Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. J. Nutr. 139:2393–2396.
   PubMed Web of Science ®Google Scholar
• Holst, B. and Williamson, G. (2004). A critical review of the bioavailability of glucosinolates and related compounds. Nat. Prod. Rep. 21:425–447.
   PubMed Web of Science ®Google Scholar
• Horn, T. L., Reichert, M. A., Bliss, R. L. and Malejka-Giganti, D. (2002). Modulations of P450 mRNA in liver and mammary gland and P450 activities and metabolism of estrogen in liver by treatment of rats with indole-3-carbinol. Biochem. Pharmacol. 64:393–404.
   PubMed Web of Science ®Google Scholar
• Hu, S., Dong, T. S., Dalal, S. R., Wu, F., Bissonnette, M., Kwon, J. H. and Chang, E. B. (2011). The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. PLoS One. 6:e16221.
   PubMed Web of Science ®Google Scholar
• Hu, S., Liu, L., Chang, E. B., Wang, J. Y. and Raufman, J. P. (2015). Butyrate inhibits pro-proliferative miR-92a by diminishing c-Myc-induced miR-17-92a cluster transcription in human colon cancer cells. Mol. Cancer. 14:180.
   PubMed Web of Science ®Google Scholar
• Hudson, E. A., Howells, L. M., Gallacher-Horley, B., Fox, L. H., Gescher, A. and Manson, M. M. (2003). Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line. BMC Cancer. 3:2.
   PubMed Web of Science ®Google Scholar
• Hutvagner, G., McLachlan, J., Pasquinelli, A. E., Balint, E., Tuschl, T. and Zamore, P. D. (2001). A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 293:834–838.
   PubMed Web of Science ®Google Scholar
• Hwang, E. S. and Kim, G. H. (2013). Effects of various heating methods on glucosinolate, carotenoid and tocopherol concentrations in broccoli. Int. J. Food Sci. Nutr. 64:103–111.
   PubMed Web of Science ®Google Scholar
• Hwang, E. S. and Lee, H. J. (2010). Effects of phenylethyl isothiocyanate and its metabolite on cell-cycle arrest and apoptosis in LNCaP human prostate cancer cells. Int. J. Food Sci. Nutr. 61:324–336.
   PubMed Web of Science ®Google Scholar
• Iwai, N. and Naraba, H. (2005). Polymorphisms in human pre-miRNAs. Biochem. Biophys. Res. Commun. 331:1439–1444.
   PubMed Web of Science ®Google Scholar
• Izzotti, A., Calin, G. A., Steele, V. E., Cartiglia, C., Longobardi, M., Croce, C. M. and De Flora, S. (2010). Chemoprevention of cigarette smoke-induced alterations of MicroRNA expression in rat lungs. Cancer Prev. Res. (Phila). 3:62–72.
   PubMed Web of Science ®Google Scholar
• Kassie, F., Uhl, M., Rabot, S., Grasl-Kraupp, B., Verkerk, R., Kundi, M., Chabicovsky, M., Schulte-Hermann, R. and Knasmuller, S. (2003). Chemoprevention of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced colonic and hepatic preneoplastic lesions in the F344 rat by cruciferous vegetables administered simultaneously with the carcinogen. Carcinogenesis. 24:255–261.
   PubMed Web of Science ®Google Scholar
• Keck, A. S. and Finley, J. W. (2004). Cruciferous vegetables: Cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr. Cancer Ther. 3:5–12.
   PubMedGoogle Scholar
• Kim, E. J., Park, S. Y., Shin, H. K., Kwon, D. Y., Surh, Y. J. and Park, J. H. (2007). Activation of caspase-8 contributes to 3,3′-Diindolylmethane-induced apoptosis in colon cancer cells. J. Nutr. 137:31–36.
   PubMed Web of Science ®Google Scholar
• Kim, J. K., Gallaher, D. D., Chen, C., Gallaher, C. M., Yao, D. and Trudo, S. P. (2016). Phenethyl isothiocyanate and indole-3-carbinol from cruciferous vegetables, but not furanocoumarins from apiaceous vegetables, reduced PhIP-induced DNA adducts in Wistar rats. Mol. Nutr. Food Res. 60:1956–1966.
   PubMed Web of Science ®Google Scholar
• Kim, N. H., Cha, Y. H., Kang, S. E., Lee, Y., Lee, I., Cha, S. Y., Ryu, J. K., Na, J. M., Park, C., Yoon, H. G., Park, G. J., Yook, J. I. and Kim, H. S. (2013). p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells. Cell Cycle. 12:1578–1587.
   PubMed Web of Science ®Google Scholar
• Kim, Y. B., Li, X., Kim, S. J., Kim, H. H., Lee, J., Kim, H. and Park, S. U. (2013). MYB transcription factors regulate glucosinolate biosynthesis in different organs of Chinese cabbage (Brassica rapa ssp. pekinensis). Molecules. 18:8682–8695.
   PubMed Web of Science ®Google Scholar
• Kopsell, D. A., Barickman, T. C., Sams, C. E. and McElroy, J. S. (2007). Influence of nitrogen and sulfur on biomass production and carotenoid and glucosinolate concentrations in watercress (Nasturtium officinale R. Br.). J. Agric. Food Chem. 55:10628–10634.
   PubMed Web of Science ®Google Scholar
• Kushad, M. M., Brown, A. F., Kurilich, A. C., Juvik, J. A., Klein, B. P., Wallig, M. A. and Jeffery, E. H. (1999). Variation of glucosinolates in vegetable crops of Brassica oleracea. J. Agric. Food Chem. 47:1541–1548.
   PubMed Web of Science ®Google Scholar
• La Rocca, G., Badin, M., Shi, B., Xu, S. Q., Deangelis, T., Sepp-Lorenzinoi, L. and Baserga, R. (2009). Mechanism of growth inhibition by MicroRNA 145: The role of the IGF-I receptor signaling pathway. J. Cell. Physiol. 220:485–491.
   PubMed Web of Science ®Google Scholar
• Lagos-Quintana, M., Rauhut, R., Lendeckel, W. and Tuschl, T. (2001). Identification of novel genes coding for small expressed RNAs. Science. 294:853–858.
   PubMed Web of Science ®Google Scholar
• Lai, K. C., Hsu, S. C., Kuo, C. L., Ip, S. W., Yang, J. S., Hsu, Y. M., Huang, H. Y., Wu, S. H. and Chung, J. G. (2010a). Phenethyl isothiocyanate inhibited tumor migration and invasion via suppressing multiple signal transduction pathways in human colon cancer HT29 cells. J. Agric. Food Chem. 58:11148–11155.
   PubMed Web of Science ®Google Scholar
• Lai, K. C., Huang, A. C., Hsu, S. C., Kuo, C. L., Yang, J. S., Wu, S. H. and Chung, J. G. (2010b). Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. J. Agric. Food Chem. 58:2935–2942.
   PubMed Web of Science ®Google Scholar
• Lai, K. C., Lu, C. C., Tang, Y. J., Chiang, J. H., Kuo, D. H., Chen, F. A., Chen, I. L. and Yang, J. S. (2014). Allyl isothiocyanate inhibits cell metastasis through suppression of the MAPK pathways in epidermal growth factorstimulated HT29 human colorectal adenocarcinoma cells. Oncol. Rep. 31:189–196.
   PubMed Web of Science ®Google Scholar
• Lam, T. K., Ruczinski, I., Helzlsouer, K. J., Shugart, Y. Y., Caulfield, L. E. and Alberg, A. J. (2010). Cruciferous vegetable intake and lung cancer risk: A nested case-control study matched on cigarette smoking. Cancer Epidemiol. Biomarkers Prev. 19:2534–2540.
   PubMed Web of Science ®Google Scholar
• Lau, W. S., Chen, T. and Wong, Y. S. (2010). Allyl isothiocyanate induces G2/M arrest in human colorectal adenocarcinoma SW620 cells through down-regulation of Cdc25B and Cdc25C. Mol. Med. Rep. 3:1023–1030.
   PubMed Web of Science ®Google Scholar
• Lee, Y., Hur, I., Park, S. Y., Kim, Y. K., Suh, M. R. and Kim, V. N. (2006). The role of PACT in the RNA silencing pathway. EMBO J. 25:522–532.
   PubMed Web of Science ®Google Scholar
• Lee, Y., Jeon, K., Lee, J. T., Kim, S. and Kim, V. N. (2002). MicroRNA maturation: Stepwise processing and subcellular localization. EMBO J. 21:4663–4670.
   PubMed Web of Science ®Google Scholar
• Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S., Baek, S. H. and Kim, V. N. (2004). MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23:4051–4060.
   PubMed Web of Science ®Google Scholar
• Leem, S. H., Li, X. J., Park, M. H., Park, B. H. and Kim, S. M. (2015). Genome-wide transcriptome analysis reveals inactivation of Wnt/beta-catenin by 3,3′-diindolylmethane inhibiting proliferation of colon cancer cells. Int. J. Oncol. 47:918–926.
   PubMed Web of Science ®Google Scholar
• Lewis, B. P., Burge, C. B. and Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20.
   PubMed Web of Science ®Google Scholar
• Li, H., Zhang, H., Lu, G., Li, Q., Gu, J., Song, Y., Gao, S. and Ding, Y. (2016). Mechanism analysis of colorectal cancer according to the microRNA expression profile. Oncol. Lett. 12:2329–2336.
   PubMed Web of Science ®Google Scholar
• Li, X. and Kushad, M. M. (2004). Correlation of glucosinolate content to myrosinase activity in horseradish (Armoracia rusticana). J. Agric. Food Chem. 52:6950–6955.
   PubMed Web of Science ®Google Scholar
• Li, Y., VandenBoom, T. G., 2nd, Kong, D., Wang, Z., Ali, S., Philip, P. A. and Sarkar, F. H. (2009). Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 69:6704–6712.
   PubMed Web of Science ®Google Scholar
• Liu, C., Teng, Z. Q., Santistevan, N. J., Szulwach, K. E., Guo, W., Jin, P. and Zhao, X. (2010). Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. 6:433–444.
   PubMed Web of Science ®Google Scholar
• Liu, X. and Lv, K. (2013). Cruciferous vegetables intake is inversely associated with risk of breast cancer: A meta-analysis. Breast. 22:309–313.
   PubMed Web of Science ®Google Scholar
• Lytle, J. R., Yario, T. A. and Steitz, J. A. (2007). Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc. Natl. Acad. Sci. U. S. A. 104:9667–9672.
   PubMed Web of Science ®Google Scholar
• Maciel-Dominguez, A., Swan, D., Ford, D. and Hesketh, J. (2013). Selenium alters miRNA profile in an intestinal cell line: Evidence that miR-185 regulates expression of GPX2 and SEPSH2. Mol. Nutr. Food Res. 57:2195–2205.
   PubMed Web of Science ®Google Scholar
• Mahn, A. and Reyes, A. (2012). An overview of health-promoting compounds of broccoli (Brassica oleracea var. italica) and the effect of processing. Food Sci. Technol. Int. 18:503–514.
   PubMed Web of Science ®Google Scholar
• Majumdar, A. P., Kodali, U. and Jaszewski, R. (2004). Chemopreventive role of folic acid in colorectal cancer. Front. Biosci. 9:2725–2732.
   PubMed Web of Science ®Google Scholar
• Marshall, J. R. (2009). Nutrition and colon cancer prevention. Curr. Opin. Clin. Nutr. Metab. Care. 12:539–543.
   PubMed Web of Science ®Google Scholar
• McIntyre, A., Gibson, P. R. and Young, G. P. (1993). Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut. 34:386–391.
   PubMed Web of Science ®Google Scholar
• Melkamu, T., Zhang, X., Tan, J., Zeng, Y. and Kassie, F. (2010). Alteration of microRNA expression in vinyl carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3-carbinol. Carcinogenesis. 31:252–258.
   PubMed Web of Science ®Google Scholar
• Meng, F., Henson, R., Wehbe-Janek, H., Ghoshal, K., Jacob, S. T. and Patel, T. (2007). MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658.
   PubMed Web of Science ®Google Scholar
• Miller-Cebert, R. L. B. J., Cebert, E., Shackelford, L. and Verghese, M. (2016). Chemopreventive potential of canola leafy greens and other cruciferous vegetables on Azoxymethane (AOM)-induced colon cancer in Fisher-344 male rats. Food Nutr. Sci. 7:964–976.
   Google Scholar
• Miranda, K. C., Huynh, T., Tay, Y., Ang, Y. S., Tam, W. L., Thomson, A. M., Lim, B. and Rigoutsos, I. (2006). A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 126:1203–1217.
   PubMed Web of Science ®Google Scholar
• Moen, B., Henjum, K., Mage, I., Knutsen, S. H., Rud, I., Hetland, R. B. and Paulsen, J. E. (2016). Effect of dietary fibers on cecal microbiota and intestinal tumorigenesis in azoxymethane treated A/J Min/+ Mice. PLoS One. 11:e0155402.
   PubMed Web of Science ®Google Scholar
• Monsma, D. J., Thorsen, P. T., Vollendorf, N. W., Crenshaw, T. D. and Marlett, J. A. (2000). In vitro fermentation of swine ileal digesta containing oat bran dietary fiber by rat cecal inocula adapted to the test fiber increases propionate production but fermentation of wheat bran ileal digesta does not produce more butyrate. J. Nutr. 130:585–593.
   PubMed Web of Science ®Google Scholar
• Moon, R. T., Kohn, A. D., De Ferrari, G. V. and Kaykas, A. (2004). WNT and beta-catenin signalling: Diseases and therapies. Nat. Rev. Genet. 5:691–701.
   PubMed Web of Science ®Google Scholar
• Motoyama, K., Inoue, H., Takatsuno, Y., Tanaka, F., Mimori, K., Uetake, H., Sugihara, K. and Mori, M. (2009). Over- and under-expressed microRNAs in human colorectal cancer. Int. J. Oncol. 34:1069–1075.
   PubMed Web of Science ®Google Scholar
• Muralidhar, B., Goldstein, L. D., Ng, G., Winder, D. M., Palmer, R. D., Gooding, E. L., Barbosa-Morais, N. L., Mukherjee, G., Thorne, N. P., Roberts, I., Pett, M. R. and Coleman, N. (2007). Global microRNA profiles in cervical squamous cell carcinoma depend on Drosha expression levels. J. Pathol. 212:368–377.
   PubMed Web of Science ®Google Scholar
• Navarro, S. L., Li, F. and Lampe, J. W. (2011). Mechanisms of action of isothiocyanates in cancer chemoprevention: An update. Food Funct. 2:579–587.
   PubMed Web of Science ®Google Scholar
• Navarro, S. L., Peterson, S., Chen, C., Makar, K. W., Schwarz, Y., King, I. B., Li, S. S., Li, L., Kestin, M. and Lampe, J. W. (2009). Cruciferous vegetable feeding alters UGT1A1 activity: Diet- and genotype-dependent changes in serum bilirubin in a controlled feeding trial. Cancer Prev. Res. (Phila). 2:345–352.
   PubMed Web of Science ®Google Scholar
• Neave, A. S., Sarup, S. M., Seidelin, M., Duus, F. and Vang, O. (2005). Characterization of the N-methoxyindole-3-carbinol (NI3C)–induced cell cycle arrest in human colon cancer cell lines. Toxicol. Sci. 83:126–135.
   PubMed Web of Science ®Google Scholar
• Nigro, N. D., Bull, A. W., Klopfer, B. A., Pak, M. S. and Campbell, R. L. (1979). Effect of dietary fiber on azoxymethane-induced intestinal carcinogenesis in rats. J. Natl. Cancer Inst. 62:1097–1102.
   PubMed Web of Science ®Google Scholar
• Nottrott, S., Simard, M. J. and Richter, J. D. (2006). Human let-7a miRNA blocks protein production on actively translating polyribosomes. Nat. Struct. Mol. Biol. 13:1108–1114.
   PubMed Web of Science ®Google Scholar
• Okamura, K., Hagen, J. W., Duan, H., Tyler, D. M. and Lai, E. C. (2007). The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell. 130:89–100.
   PubMed Web of Science ®Google Scholar
• Ozcan, O., Kara, M., Yumrutas, O., Bozgeyik, E., Bozgeyik, I. and Celik, O. I. (2016). MTUS1 and its targeting miRNAs in colorectal carcinoma: Significant associations. Tumour Biol. 37:6637–6645.
   PubMed Web of Science ®Google Scholar
• Padilla, G., Cartea, M. E., Velasco, P., de Haro, A. and Ordas, A. (2007). Variation of glucosinolates in vegetable crops of Brassica rapa. Phytochemistry. 68:536–545.
   PubMed Web of Science ®Google Scholar
• Padua, D. and Massague, J. (2009). Roles of TGFbeta in metastasis. Cell Res. 19:89–102.
   PubMed Web of Science ®Google Scholar
• Paik, W. H., Kim, H. R., Park, J. K., Song, B. J., Lee, S. H. and Hwang, J. H. (2013). Chemosensitivity induced by down-regulation of microRNA-21 in gemcitabine-resistant pancreatic cancer cells by indole-3-carbinol. Anticancer Res. 33:1473–1481.
   PubMed Web of Science ®Google Scholar
• Park, W. T., Kim, J. K., Park, S., Lee, S. W., Li, X., Kim, Y. B., Uddin, M. R., Park, N. I., Kim, S. J. and Park, S. U. (2012). Metabolic profiling of glucosinolates, anthocyanins, carotenoids, and other secondary metabolites in kohlrabi (Brassica oleracea var. gongylodes). J. Agric. Food Chem. 60:8111–8116.
   PubMed Web of Science ®Google Scholar
• Parnaud, G., Li, P., Cassar, G., Rouimi, P., Tulliez, J., Combaret, L. and Gamet-Payrastre, L. (2004). Mechanism of sulforaphane-induced cell cycle arrest and apoptosis in human colon cancer cells. Nutr. Cancer. 48:198–206.
   PubMed Web of Science ®Google Scholar
• Pastrello, C., Tsay, M., McQuaid, R., Abovsky, M., Pasini, E., Shirdel, E., Angeli, M., Tokar, T., Jamnik, J., Kotlyar, M., Jurisicova, A., Kotsopoulos, J., El-Sohemy, A. and Jurisica, I. (2016). Circulating plant miRNAs can regulate human gene expression in vitro. Sci. Rep. 6:32773.
   PubMed Web of Science ®Google Scholar
• Petersen, C. P., Bordeleau, M. E., Pelletier, J. and Sharp, P. A. (2006). Short RNAs repress translation after initiation in mammalian cells. Mol. Cell. 21:533–542.
   PubMed Web of Science ®Google Scholar
• Pierre, F., Tache, S., Petit, C. R., Van der Meer, R. and Corpet, D. E. (2003). Meat and cancer: Haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats. Carcinogenesis. 24:1683–1690.
   PubMed Web of Science ®Google Scholar
• Pillai, R. S., Bhattacharyya, S. N., Artus, C. G., Zoller, T., Cougot, N., Basyuk, E., Bertrand, E. and Filipowicz, W. (2005). Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science. 309:1573–1576.
   PubMed Web of Science ®Google Scholar
• Place, R. F., Li, L. C., Pookot, D., Noonan, E. J. and Dahiya, R. (2008). MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl. Acad. Sci. U. S. A. 105:1608–1613.
   PubMed Web of Science ®Google Scholar
• Pogue, A. I., Cui, J. G., Li, Y. Y., Zhao, Y., Culicchia, F. and Lukiw, W. J. (2010). Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neurosci. Lett. 476:18–22.
   PubMed Web of Science ®Google Scholar
• Poy, M. N., Eliasson, L., Krutzfeldt, J., Kuwajima, S., Ma, X., Macdonald, P. E., Pfeffer, S., Tuschl, T., Rajewsky, N., Rorsman, P. and Stoffel, M. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 432:226–230.
   PubMed Web of Science ®Google Scholar
• Qian, H., Sun, B., Miao, H., Cai, C., Xu, C. and Wang, Q. (2015). Variation of glucosinolates and quinone reductase activity among different varieties of Chinese kale and improvement of glucoraphanin by metabolic engineering. Food Chem. 168:321–326.
   PubMed Web of Science ®Google Scholar
• Rajendran, P., Dashwood, W. M., Li, L., Kang, Y., Kim, E., Johnson, G., Fischer, K. A., Lohr, C. V., Williams, D. E., Ho, E., Yamamoto, M., Lieberman, D. A. and Dashwood, R. H. (2015). Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon. Clin. Epigenetics. 7:102.
   PubMed Web of Science ®Google Scholar
• Reeves, M. A. and Hoffmann, P. R. (2009). The human selenoproteome: Recent insights into functions and regulation. Cell. Mol. Life Sci. 66:2457–2478.
   PubMed Web of Science ®Google Scholar
• Robbins, M. G., Hauder, J., Somoza, V., Eshelman, B. D., Barnes, D. M. and Hanlon, P. R. (2010). Induction of detoxification enzymes by feeding unblanched Brussels sprouts containing active myrosinase to mice for 2 wk. J. Food Sci. 75:H190–199.
   PubMed Web of Science ®Google Scholar
• Safe, S. (2001). Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol. Lett. 120:1–7.
   PubMed Web of Science ®Google Scholar
• Sakamoto, S., Aoki, K., Higuchi, T., Todaka, H., Morisawa, K., Tamaki, N., Hatano, E., Fukushima, A., Taniguchi, T. and Agata, Y. (2009). The NF90-NF45 complex functions as a negative regulator in the microRNA processing pathway. Mol. Cell. Biol. 29:3754–3769.
   PubMed Web of Science ®Google Scholar
• Sanz-Pamplona, R., Cordero, D., Berenguer, A., Lejbkowicz, F., Rennert, H., Salazar, R., Biondo, S., Sanjuan, X., Pujana, M. A., Rozek, L., Giordano, T. J., Ben-Izhak, O., Cohen, H. I., Trougouboff, P., Bejhar, J., Sova, Y., Rennert, G., Gruber, S. B. and Moreno, V. (2011). Gene expression differences between colon and rectum tumors. Clin. Cancer Res. 17:7303–7312.
   PubMed Web of Science ®Google Scholar
• Schatzkin, A., Mouw, T., Park, Y., Subar, A. F., Kipnis, V., Hollenbeck, A., Leitzmann, M. F. and Thompson, F. E. (2007). Dietary fiber and whole-grain consumption in relation to colorectal cancer in the NIH-AARP Diet and Health Study. Am. J. Clin. Nutr. 85:1353–1360.
   PubMed Web of Science ®Google Scholar
• Shibuya, H., Iinuma, H., Shimada, R., Horiuchi, A. and Watanabe, T. (2010). Clinicopathological and prognostic value of microRNA-21 and microRNA-155 in colorectal cancer. Oncology. 79:313–320.
   PubMed Web of Science ®Google Scholar
• Slaby, O., Sachlova, M., Brezkova, V., Hezova, R., Kovarikova, A., Bischofova, S., Sevcikova, S., Bienertova-Vasku, J., Vasku, A., Svoboda, M. and Vyzula, R. (2013). Identification of microRNAs regulated by isothiocyanates and association of polymorphisms inside their target sites with risk of sporadic colorectal cancer. Nutr. Cancer. 65:247–254.
   PubMed Web of Science ®Google Scholar
• Stark, K. L., Xu, B., Bagchi, A., Lai, W. S., Liu, H., Hsu, R., Wan, X., Pavlidis, P., Mills, A. A., Karayiorgou, M. and Gogos, J. A. (2008). Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40:751–760.
   PubMed Web of Science ®Google Scholar
• Tang, L., Zirpoli, G. R., Jayaprakash, V., Reid, M. E., McCann, S. E., Nwogu, C. E., Zhang, Y., Ambrosone, C. B. and Moysich, K. B. (2010). Cruciferous vegetable intake is inversely associated with lung cancer risk among smokers: A case-control study. BMC Cancer. 10:162.
   PubMed Web of Science ®Google Scholar
• Vale, A. P., Santos, J., Brito, N. V., Fernandes, D., Rosa, E. and Oliveira, M. B. (2015). Evaluating the impact of sprouting conditions on the glucosinolate content of Brassica oleracea sprouts. Phytochemistry. 115:252–260.
   PubMed Web of Science ®Google Scholar
• Vang, O., Frandsen, H., Hansen, K. T., Sorensen, J. N., Sorensen, H. and Andersen, O. (2001). Biochemical effects of dietary intakes of different broccoli samples. I. Differential modulation of cytochrome P-450 activities in rat liver, kidney, and colon. Metabolism. 50:1123–1129.
   PubMed Web of Science ®Google Scholar
• Vargas, A. J. and Thompson, P. A. (2012). Diet and nutrient factors in colorectal cancer risk. Nutr. Clin. Pract. 27:613–623.
   PubMed Web of Science ®Google Scholar
• Vella, M. C., Choi, E. Y., Lin, S. Y., Reinert, K. and Slack, F. J. (2004). The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3′UTR. Genes Dev. 18:132–137.
   PubMed Web of Science ®Google Scholar
• Walters, D. G., Young, P. J., Agus, C., Knize, M. G., Boobis, A. R., Gooderham, N. J. and Lake, B. G. (2004). Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. Carcinogenesis. 25:1659–1669.
   PubMed Web of Science ®Google Scholar
• Wang, X., He, H., Lu, Y., Ren, W., Teng, K. Y., Chiang, C. L., Yang, Z., Yu, B., Hsu, S., Jacob, S. T., Ghoshal, K. and Lee, L. J. (2015). Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog. Biochim. Biophys. Acta. 1853:244–253.
   PubMed Web of Science ®Google Scholar
• Weng, J. R., Tsai, C. H., Kulp, S. K. and Chen, C. S. (2008). Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 262:153–163.
   PubMed Web of Science ®Google Scholar
• Wilfred, B. R., Wang, W. X. and Nelson, P. T. (2007). Energizing miRNA research: A review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol. Genet. Metab. 91:209–217.
   PubMed Web of Science ®Google Scholar
• Wolf, C. R. (2001). Chemoprevention: Increased potential to bear fruit. Proc. Natl. Acad. Sci. U. S. A. 98:2941–2943.
   PubMed Web of Science ®Google Scholar
• Wu, L., Fan, J. and Belasco, J. G. (2006). MicroRNAs direct rapid deadenylation of mRNA. Proc. Natl. Acad. Sci. U. S. A. 103:4034–4039.
   PubMed Web of Science ®Google Scholar
• Wu, Q. J., Yang, Y., Vogtmann, E., Wang, J., Han, L. H., Li, H. L. and Xiang, Y. B. (2013). Cruciferous vegetables intake and the risk of colorectal cancer: A meta-analysis of observational studies. Ann. Oncol. 24:1079–1087.
   PubMed Web of Science ®Google Scholar
• Xing, Y., Liu, Z., Yang, G., Gao, D. and Niu, X. (2015). MicroRNA expression profiles in rats with selenium deficiency and the possible role of the Wnt/beta-catenin signaling pathway in cardiac dysfunction. Int. J. Mol. Med. 35:143–152.
   PubMed Web of Science ®Google Scholar
• Yang, B., Lin, H., Xiao, J., Lu, Y., Luo, X., Li, B., Zhang, Y., Xu, C., Bai, Y., Wang, H., Chen, G. and Wang, Z. (2007). The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat. Med. 13:486–491.
   PubMed Web of Science ®Google Scholar
• Yi, G., Lim, S., Chae, W. B., Park, J. E., Park, H. R., Lee, E. J. and Huh, J. H. (2016). Root glucosinolate profiles for screening of radish (Raphanus sativus L.) genetic resources. J. Agric. Food Chem. 64:61–70.
   PubMed Web of Science ®Google Scholar
• Yi, G. E., Robin, A. H., Yang, K., Park, J. I., Kang, J. G., Yang, T. J. and Nou, I. S. (2015). Identification and expression analysis of glucosinolate biosynthetic genes and estimation of glucosinolate contents in edible organs of Brassica oleracea subspecies. Molecules. 20:13089–13111.
   PubMed Web of Science ®Google Scholar
• Yi, R., Doehle, B. P., Qin, Y., Macara, I. G. and Cullen, B. R. (2005). Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs. RNA. 11:220–226.
   PubMed Web of Science ®Google Scholar
• You, Z., Saims, D., Chen, S., Zhang, Z., Guttridge, D. C., Guan, K. L., MacDougald, O. A., Brown, A. M., Evan, G., Kitajewski, J. and Wang, C. Y. (2002). Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J. Cell Biol. 157:429–440.
   PubMed Web of Science ®Google Scholar
• Yuan, B., Dong, R., Shi, D., Zhou, Y., Zhao, Y., Miao, M. and Jiao, B. (2011). Down-regulation of miR-23b may contribute to activation of the TGF-beta1/Smad3 signalling pathway during the termination stage of liver regeneration. FEBS Lett. 585:927–934.
   PubMed Web of Science ®Google Scholar
• Zhang, G., Zhou, H., Xiao, H., Liu, Z., Tian, H. and Zhou, T. (2014). MicroRNA-92a functions as an oncogene in colorectal cancer by targeting PTEN. Dig. Dis. Sci. 59:98–107.
   PubMed Web of Science ®Google Scholar
• Zhang, H., Hao, Y., Yang, J., Zhou, Y., Li, J., Yin, S., Sun, C., Ma, M., Huang, Y. and Xi, J. J. (2011). Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis. Nat. Commun. 2:554.
   PubMed Web of Science ®Google Scholar
• Zheng, Q., Hirose, Y., Yoshimi, N., Murakami, A., Koshimizu, K., Ohigashi, H., Sakata, K., Matsumoto, Y., Sayama, Y. and Mori, H. (2002). Further investigation of the modifying effect of various chemopreventive agents on apoptosis and cell proliferation in human colon cancer cells. J. Cancer Res. Clin. Oncol. 128:539–546.
   PubMed Web of Science ®Google Scholar
• Zhu, C., Poulsen, H. E. and Loft, S. (2000). Inhibition of oxidative DNA damage in vitro by extracts of brussels sprouts. Free Radic. Res. 33:187–196.
   PubMed Web of Science ®Google Scholar