偶氮甲烷
酪蛋白激酶1
Wnt信号通路
结直肠癌
磷酸化
Janus激酶2
连环蛋白
连环素
癌变
激酶
癌症研究
癌症
信号转导
细胞生物学
生物
蛋白激酶A
遗传学
作者
Yuyuan Zi,Liyu Liu,Jie Gao,Xu Xu,Yifu Guan,Zhuoxian Rong,Zhiyuan Cao,Mengwei Li,Zimei Zeng,Qi-Wen Fan,Feiyu Tang,Junyang He,Dan Feng,Jionghuang Chen,Yawei Dai,Yufeng Huang,Yingjie Nie,Haiping Pei,Qing-Qing Cai,Zhi Li,Lun‐Quan Sun,Yu Deng
标识
DOI:10.15252/embr.202255060
摘要
Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to β-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1α (CK1α), thereby disrupting its binding to Axin, disassociating the β-catenin destruction complex, decreasing the phosphorylation of β-catenin, and activating the Wnt/β-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/β-catenin signaling pathway, providing a potential novel therapeutic target.
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