Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/26/2011
Publication Date: 9/1/2011
Citation: Liu, Z., Ciappio, E.D., Crott, J.W., Brooks, R.S., Nesvet, J., Smith, D.E., Choi, S., Mason, J.B. 2011. Combined inadequacies of multiple B-vitamins amplify colonic Wnt-signaling and promote intestinal tumorigenesis in BAT-LacZxApc1368N mice. Journal of Federation of American Societies for Experimental Biology. 25(9):3136-3145. Interpretive Summary: Accumulating evidence indicates that habitual dietary intake of folate is inversely related to the risk of developing colorectal cancer. This concept possesses a great deal of plausibility since folate is an essential co-factor for making new DNA and protecting existing DNA, and it is well known that factors that interfere with the integrity of DNA are likely to increase the risk of cancer. Folate may therefore have an important role to play in the prevention of this common cancer. However, the intelligent design of strategies that utilize folate for cancer prevention require a mechanistic understanding of how folate exerts it effects on specific cellular pathways. Furthermore, biochemical functions of folate are dependent on the adequate availability of other ‘one-carbon nutrients’, including vitamins B2, B6 and B12, but the synergistic effect of these B-vitamins is unknown. This study demonstrates that mild inadequacies of several B-vitamins amplify a critical pro-cancerous pathway, the so-called ‘Wnt pathway’, and promotes the development of intestinal cancers. The results advanced our mechanistic understanding of the phenomenon and thereby facilitates our ability to develop cancer preventive strategies.
Technical Abstract: The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically-related one-carbon vitamins induces in vivo activation of intestinal Wnt signaling, and whether this occurs in parallel with increased tumorigenesis. A hybrid mouse was created by crossing a Wnt-reporter animal (BAT-LacZ) with a model of colorectal cancer (Apc1638N). A mild depletion of folate, and vitamins B2, B6 and B12 was induced over 16 weeks, and the control animals in each instance were pair-fed a diet containing the basal requirement of these nutrients. The results indicate multiplicity of macroscopic tumors and aberrant crypt foci both increased by ~50% in the hybrid mice fed the depletion diet (p < 0.05). A 4-fold elevation in Wnt signaling was produced by the deplete diet (p<0.05), and was accompanied by significant changes in the expression of a number of Wnt-related genes in a pattern consistent with its activation. Proliferation and apoptosis of the colonic mucosa both changed in a pro-transformational direction (p<0.05). In summary, mild depletion of one-carbon vitamins produces in vivo activation of colonic Wnt-signaling, implicating it as a key pathway by which one-carbon vitamin inadequacies enhance intestinal tumorigenesis.