Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China.
Department of Gastroenterology, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, People's Republic of China.
Cell Commun Signal. 2022 May 25;20(1):71. doi: 10.1186/s12964-022-00890-8.
Cholecystectomy (XGB) is widely recognized as a risk factor for colon cancer (CC). Continuous exposure of the colonic epithelium to deoxycholic acid (DCA) post-XGB may exert cytotoxic effects and be involved in the progression of CC. However, the functions of the XGB-induced DCA increase and the underlying mechanism remain unclear.
Colitis-associated CC (CAC) mouse models constructed by AOM-DSS inducement were used to confirm the effect of XGB on the CC progression. Hematoxylin & eosin staining was performed to assess the tumor morphology of CAC mouse models tissues. Various cell biological assays including EdU, live-cell imaging, wound-healing assays, and flow cytometry for cell cycle and apoptosis were used to evaluate the effect of DCA on CC progression. The correlation among XGB, DCA, and CC and their underlying mechanisms were detected with immunohistochemistry, mass spectrometry, transcriptome sequencing, qRT-PCR, and western blotting.
Here we proved that XGB increased the plasma DCA level and promoted colon carcinogenesis in a colitis-associated CC mouse model. Additionally, we revealed that DCA promoted the proliferation and migration of CC cells. Further RNA sequencing showed that 120 mRNAs were upregulated, and 118 downregulated in DCA-treated CC cells versus control cells. The upregulated mRNAs were positively correlated with Wnt signaling and cell cycle-associated pathways. Moreover, DCA treatment could reduced the expression of the farnesoid X receptor (FXR) and subsequently increased the levels of β-Catenin and c-Myc in vitro and in vivo. Moreover, the FXR agonist GW4064 decreased the proliferation of CC cells by repressing the expression of β-catenin.
We concluded that XGB-induced DCA exposure could promote the progression of CC by inhibiting FXR expression and enhancing the Wnt-β-catenin pathway. Video Abstract.
胆囊切除术（XGB）被广泛认为是结肠癌（CC）的危险因素。XGB 后，脱氧胆酸（DCA）持续暴露于结肠上皮可能会产生细胞毒性作用，并参与 CC 的进展。然而，XGB 诱导的 DCA 增加的功能及其潜在机制尚不清楚。
使用 AOM-DSS 诱导的结肠炎相关结肠癌（CAC）小鼠模型来证实 XGB 对 CC 进展的影响。苏木精和伊红染色用于评估 CAC 小鼠模型组织的肿瘤形态。各种细胞生物学测定，包括 EdU、活细胞成像、划痕愈合测定和细胞周期和凋亡的流式细胞术，用于评估 DCA 对 CC 进展的影响。通过免疫组织化学、质谱、转录组测序、qRT-PCR 和 Western blot 检测 XGB、DCA 和 CC 之间的相关性及其潜在机制。
我们证明 XGB 增加了血浆 DCA 水平，并在结肠炎相关 CC 小鼠模型中促进了结肠癌的发生。此外，我们发现 DCA 促进了 CC 细胞的增殖和迁移。进一步的 RNA 测序显示，在 DCA 处理的 CC 细胞与对照细胞中，有 120 个 mRNA 上调，118 个下调。上调的 mRNA 与 Wnt 信号通路和细胞周期相关途径呈正相关。此外，DCA 处理可以降低法尼醇 X 受体（FXR）的表达，从而在体外和体内增加β-Catenin 和 c-Myc 的水平。此外，FXR 激动剂 GW4064 通过抑制β-catenin 的表达来减少 CC 细胞的增殖。
我们得出结论，XGB 诱导的 DCA 暴露可以通过抑制 FXR 表达和增强 Wnt-β-catenin 途径来促进 CC 的进展。
