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Author ORCID Identifier
Open Access Dissertation
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Molecular, Genetic, and Biochemical Nutrition
Colorectal cancer (CRC) is the third leading cause of cancer deaths in the United States. A number of population studies have established that modifiable lifestyle factors such as obesity plays an important role in colorectal carcinogenesis. In the United States, more than one-third of adults are obese and obesity prevalence rates have no sign of decrease. Therefore, the development of effective strategies to prevent obesity-induced CRC is a public health priority. This study aimed to investigate whether genetic or dietary strategies can prevent obesity-induced CRC and determine the potential molecular mechanisms underlying the prevention effects of these strategies. We used Apc1638N mice, germline heterozygous mutation in the Apc gene, and Caco-2 cell line to study intestinal tumorigenesis. Hematoxylin and eosin stain and QuickPlex SQ 120, a chemiluminescence assay, were used to measure the inflammatory status. Real-time PCR, Western blot assay, and immunohistochemical analysis were used to further examine the signaling pathway status. We found that loss of Tumor necrosis factor alpha (TNF-α) decreased obesity associated intestinal tumorigenesis by decreasing the inflammation, and manipulating the β-catenin pathway and NF-kB signaling. In addition, IKK, a component of the NF-kB signaling, was involved in the regulation of β-catenin pathway. The administration of Vitamin D (VD), at 5000 IU level, exerted an anti-inflammatory property and led to suppressed intestinal Wnt-signaling and tumorigenesis in obese mice. The molecular function of sulforaphane (SFN) on a high dose of VD supplementation, although displayed on the inhibition of HDAC and the activation of autophagy, needs further investigation. Butyrate can increase the activity of Wnt/β-catenin pathway. Knocking down FFAR2 by siRNA decreased the expression of cleaved caspase 3 and the expression of phospho-GSK3β (Ser9) and active β-catenin in Caco-2 cells, subsequently mitigated the anticancer effect of butyrate.
Li, Jinchao, "THE PREVENTION OF OBESITY-ASSOCIATED COLORECTAL CANCER VIA DIETARY SUPPRESSION OF INFLAMMATION-DRIVEN WNT-SIGNALING" (2019). Doctoral Dissertations. 1600.