Dietary-induced ERbeta upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice.
Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ERbeta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERbeta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ERbeta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERbeta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ERbeta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ERbeta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ERbeta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.
Barone
Michele
M
Department of Emergency and Organ Transplantation, University of Bari, Ospedale Policlinico, Bari, Italy.
Tanzi
Sabina
S
Lofano
Katia
K
Scavo
Maria Principia
MP
Pricci
Maria
M
Demarinis
Lucia
L
Papagni
Samanta
S
Guido
Raffaella
R
Maiorano
Eugenio
E
Ingravallo
Giuseppe
G
Comelli
Maria Cristina
MC
Francavilla
Antonio
A
Di Leo
Alfredo
A
D000236:Adenoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D004032:Diet; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007414:Intestinal Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D007417:Intestinal Polyps / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D025601:Adenomatous Polyposis Coli Protein; D047629:Estrogen Receptor beta; D012333:RNA, Messenger