Dvl2 facilitates the coordination of NF-κB and Wnt signaling to promote colitis-associated colorectal progression.
Dvl2 facilitates the coordination of NF-κB and Wnt signaling to promote colitis-associated colorectal progression.
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Dvl2 促进 NF-kappa B 和 Wnt 信号传导的协调，促进结肠炎相关的结直肠进展
DOI：
10.1111/cas.15206
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发表时间：
2022-03
期刊：
影响因子：
5.7
通讯作者：
Sun L
中科院分区：
文献类型：
--
作者：
Tang F;Cao F;Lu C;He X;Weng L;Sun L
结肠炎相关的结直肠癌（CAC）是由于持续的感染而引起的，并且与零星的结直肠癌相比（CRC）。这2之间的调节途径不清楚。 YTOSIS，导致NF-κB信号的抑制作用。促炎的细胞因子白介素13（IL-13）负责通过STAT6上调DVL2表达，从而有效地降低了DVL2水平，并限制了癌细胞的菌落形成。
DVL2和NF -κB信号传导激活之间的强反向关联在TNFRI内吞作用中起着强烈的作用，并且可能是TNFRI – NF -κB和Wnt信号传导炎症的分子连接。
Colitis‐associated colorectal cancer (CAC) arises due to prolonged inflammation and has distinct molecular events compared with sporadic colorectal cancer (CRC). Although inflammatory NF‐κB signaling was activated by pro‐inflammatory cytokines (such as TNFα) in early stages of CAC, Wnt/β‐catenin signaling later appears to function as a key regulator of CAC progression. However, the exact mechanism responsible for the cross‐regulation between these 2 pathways remains unclear. Here, we found reciprocal inhibition between NF‐κB and Wnt/β‐catenin signaling in CAC samples, and the Dvl2, an adaptor protein of Wnt/β‐catenin signaling, is responsible for NF‐κB inhibition. Mechanistically, Dvl2 interacts with the C‐terminus of tumor necrosis factor receptor 1 (TNFRI) and mediates TNFRI endocytosis, leading to NF‐κB signal inhibition. In addition, increased infiltration of the pro‐inflammatory cytokine interleukin‐13 (IL‐13) is responsible for upregulating Dvl2 expression through STAT6. Targeting STAT6 effectively decreases Dvl2 levels and restrains colony formation of cancer cells. These findings demonstrate a unique role for Dvl2 in TNFRI endocytosis, which facilitates the coordination of NF‐κB and Wnt to promote CAC progression. Strong reverse associations between Dvl2 and NF‐κB signaling activation. Dvl2 plays a strong role in TNFRI endocytosis and could be a molecular connection between the TNFRI–NF‐κB and Wnt signaling inflammatory microenvironment of tumors for the transcriptional level of Dvl2.
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