ERK activation drives intestinal tumorigenesis in Apc(min/+) mice (Nat Med, 2010, 16:665-670)

報告日期: 2010/10/22
報告時間: 16:00/16:50
報告學生: 陳雅均
講評老師: 洪建中

Full text:

ERK activation drives intestinal tumorigenesis in Apcmin/+ mice


SourceNat Med 2010, 16(6):665-70.

AuthorsSung Hee Lee, Li-Li Hu, Jose Gonzalez-Navajas,





Apc (adenomatous polyposis coli) gene is mutated in up to 80% of sporadic colorectal cancers. Lost of APC results in the activation of β-catenin/Tcf4 transcription complex that turns on genes such as C-Myc and cyclin D1 for cell proliferation. Deletion of Myc inhibits tumor growth in intestinal epithelial cells (IEC) of Apcmin (multiple intestinal neoplasia)/+ mice. In addition, several study indicated that the gastro- intestinal tract tumor is associated with bacterial infection and/or inflammatory products, suggesting Toll-like receptor(TLR)-MyD88 signaling pathway might regulate IEC tumorgenesis in mice with Apc mutation. However, the underlying mechanism of TLR signaling to Myc expression was not identified. To address this issue, the authors demonstrated that genetic deletion of MyD88 in Apcmin/+ mice significantly lower the polyp incidence in the colon/distal small intestine and the survival of mice. Therefore, MyD88 signaling is essential for polyps growing in Apcmin/+ mice. Results from Br-dU incorporation and TUNEL analysis indicates MyD88 is required for increased cell proliferation and decreased apoptosis of IEC in Apcmin/+ mice. In addition, deletion of MyD88 reduces the expression of c-Myc and p-ERK in both cultured cells and mice. As proteasome inhibitor MG-132 increases c-Myc protein, but not its mRNA in colorectal cancer cell RKO, they further demonstrate Myc is under ubiquitination in the presence of ERK inhibitor or MyD88 deficiency. Besides, inhibition of the ERK pathway in Apcmin/+ mice reduces intestinal tumorigenesis via decreased expression of Myc. Collectivity, the authors demonstrate that microflora-MyD88-ERK signaling in IEC promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein.



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