RESUMEN
Human epidemiological evidence and previous studies on mice have shown that Western-style diet (WD) may predispose gut mucosa to colorectal cancer (CRC). The mechanisms that mediate the effects of diet on tumorigenesis are largely unknown. To address putative cancer-predisposing events available for early detection, we quantitatively analyzed the proteome of histologically normal colon of a wild-type (Mlh1(+/+)) and an Mlh1(+/-) mouse after a long-term feeding experiment with WD and AIN-93G control diet. The Mlh1(+/-) mouse carries susceptibility to colon cancer analogous to a human CRC syndrome (Lynch syndrome). Remarkably, WD induced expression changes reflecting metabolic disturbances especially in the cancer-predisposed colon, while similar changes were not significant in the wild-type proteome. Overall, the detected changes constitute a complex interaction network of proteins involved in ATP synthesis coupled proton transport, oxidoreduction coenzyme and nicotinamide nucleotide metabolic processes, important in cell protection against reactive oxygen species toxicity. Of these proteins, selenium binding protein 1 and galectin-4, which directly interact with MutL homolog 1, are underlined in neoplastic processes, suggesting that sensitivity to WD is increased by an Mlh1 mutation. The significance of WD on CRC risk is highlighted by the fact that five out of six mice with neoplasias were fed with WD.
Asunto(s)
Neoplasias Colorrectales/genética , Dieta , Predisposición Genética a la Enfermedad , Mucosa Intestinal/patología , Proteoma , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/fisiología , Animales , Western Blotting , Neoplasias Colorrectales/metabolismo , Ácidos Grasos/metabolismo , Glucosa/administración & dosificación , Ratones , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Aumento de PesoRESUMEN
Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1(+/-) mice, an animal model for human Lynch syndrome (LS), and wild type Mlh1(+/+) littermates, fed by either Western-style (WD) or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1(+/-) mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold) together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1(+/-) and Mlh1(+/+) mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Colon/metabolismo , Neoplasias del Colon/genética , Dieta Alta en Grasa , Regulación Neoplásica de la Expresión Génica , Membrana Mucosa/metabolismo , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Animales , Proteínas de Transporte de Catión/genética , Colon/patología , Neoplasias del Colon/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Metilación de ADN , Modelos Animales de Enfermedad , Proteínas de Homeodominio/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos , Membrana Mucosa/patología , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/deficiencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Factores de TiempoRESUMEN
Multiple kernel learning (MKL) partially solves the kernel selection problem in support vector machines and similar classifiers by minimizing the empirical risk over a subset of the linear combination of given kernel matrices. For large sample sets, the size of the kernel matrices becomes a numerical issue. In many cases, the kernel matrix is of low-efficient rank. However, the low-rank property is not efficiently utilized in MKL algorithms. Here, we suggest multiple spectral kernel learning that efficiently uses the low-rank property by finding a kernel matrix from a set of Gram matrices of a few eigenvectors from all given kernel matrices, called a spectral kernel set. We provide a new bound for the gaussian complexity of the proposed kernel set, which depends on both the geometry of the kernel set and the number of Gram matrices. This characterization of the complexity implies that in an MKL setting, adding more kernels may not monotonically increase the complexity, while previous bounds show otherwise.
