Abstract
Inflammatory activation and intestinal flora imbalance play an essential role in the development and progression of colorectal cancer (CRC). Berberine (BBR) has attracted great attention in recent years due to its heath-related benefits in inflammatory disorders and tumors, but the intricate mechanisms have not been fully elucidated. In this study, the effects and the mechanism of BBR on colon cancer were investigated in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis mice model. Our results showed that pre-administration of BBR showed a decrease in weight loss, disease activity index (DAI) score, and the number of colon tumors in mice, compared with the model group. The evidence from pathological examination indicated that the malignancy of intestinal tumors was ameliorated after pre-administration of BBR. Additionally, pre-administration with BBR suppressed the expression of pro-inflammatory factors (interleukin (IL)-6, IL-1β, cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)-α) and the cell-proliferation marker Ki67, while expression of the tight junction proteins (ZO-1 and occludin) were increased in colon tissue. Moreover, the levels of critical pathway proteins involved in the inflammatory process (p-STAT3 and p-JNK) and cell cycle regulation molecules (β-catenin, c-Myc and CylinD1) exhibited lower expression levels. Besides, 16S rRNA sequence analysis indicated that pre-administration of BBR increased the ratio of Firmicutes/Bacteroidetes (F:M) and the relative abundance of potentially beneficial bacteria, while the abundance of cancer-related bacteria was decreased. Gavage with Lactobacillus rhamnosus can improve the anti-tumor effect of BBR. Overall, pre-administration of BBR exerts preventive effects in colon carcinogenesis, and the mechanisms underlying these effects are correlated with the inhibition of inflammation and tumor proliferation and the maintenance of intestinal homeostasis.
Highlights
Colorectal cancer (CRC) is one of the most frequent malignant tumors in the digestive tract with a complex etiology and high fatality rate, and it is correlated to lifestyle factors, including low physical activity, high-fat diets, alcohol consumption, smoking tobacco and sedentary behavior [1,2]
Several studies have demonstrated that inflammatory bowel disease (IBD) caused by chronic inflammatory conditions can increase the risk of CRC, such as ulcerative colitis (UC) and Crohn’s disease (CD) [3,4]
In order to investigate the effect of BBR on dextran sodium sulfate (DSS)-induced colitis mice, the body weights of mice were examined in each group
Summary
Colorectal cancer (CRC) is one of the most frequent malignant tumors in the digestive tract with a complex etiology and high fatality rate, and it is correlated to lifestyle factors, including low physical activity, high-fat diets, alcohol consumption, smoking tobacco and sedentary behavior [1,2]. Several studies have demonstrated that inflammatory bowel disease (IBD) caused by chronic inflammatory conditions can increase the risk of CRC, such as ulcerative colitis (UC) and Crohn’s disease (CD) [3,4]. Multiple interrelated pathways were considered to be involved in the pathogenesis of IBD-associated CRC, including inflammatory response, oxidative stress, and intestinal microbiota [3,5]. Inflammatory response is driven by inflammatory cytokines, which are generated by tumor cells and the immune cells from tumor microenvironment. Accumulating evidence has demonstrated that inflammatory cytokines can enhance cancer cell growth rates and invasiveness through activating inflammatory signaling pathways, including NF-κB and STATs [8,9]. Wnt/β-catenin signaling has been considered to be an indispensable player in tumorigenesis with its regulatory role on the inflammatory cascade [10]
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