Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers.
Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers.
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DOI：
10.1038/s41598-018-20572-1
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发表时间：
2018-02-02
影响因子：
4.6
通讯作者：
Ohki R
中科院分区：
文献类型：
--
作者：
Ohtsuka J;Oshima H;Ezawa I;Abe R;Oshima M;Ohki R
p53 突变经常在恶性胃癌中检测到。然而，p53功能丧失促进胃癌的分子机制尚不清楚。我们利用具有功能性 p53 并发生肠型胃肿瘤的 Gan 小鼠 (K19-Wnt1/C2mE)，通过敲除 p53 来研究 p53 在胃癌进展中的作用。我们发现，由于 Wnt 激活、COX-2 激活和 p53 缺陷，胃上皮细胞在 C57BL/6 小鼠皮下组织中获得致瘤性。随着反复的同种异体移植，这些胃上皮细胞逐渐获得了恶性胃癌的特性。 p53的缺失赋予细胞干性并诱导胃上皮细胞上皮间质转化（EMT），这些特性通过体内微环境进一步增强，最终导致胃癌的形成和转移。我们还发现体内微环境增强了 COX-2 通路的激活，这进一步促进了癌症的进展。通过这个系统，我们成功地再现了正常免疫环境下胃上皮细胞恶性胃癌的发展过程。
p53 mutations are frequently detected in malignant gastric cancers. However, the molecular mechanisms by which loss of p53 function promotes gastric cancer are not clear. We utilized Gan mice (K19-Wnt1/C2mE), which have functional p53 and develop intestinal-type gastric tumors, to investigate the role of p53 in gastric cancer progression by knocking out p53. We found that gastric epithelial cells acquire tumorigenicity in the subcutis of C57BL/6 mice as a result of Wnt activation, COX-2 activation and p53 deficiency. With repeated allograft transfers, these gastric epithelial cells gradually acquired the properties of malignant gastric cancer. Loss of p53 conferred cell stemness and induced epithelial to mesenchymal transition (EMT) in gastric epithelial cells, and these properties were further enhanced by the in vivo microenvironment, ultimately leading to gastric cancer formation and metastasis. We also found that the in vivo microenvironment enhanced activation of the COX-2 pathway, which further contributed to cancer progression. With this system, we have succeeded in recapitulating the development of malignant gastric cancer from gastric epithelial cells in a normal immune environment.
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影响因子：
29.4
作者：
Wang F;Scoville D;He XC;Mahe MM;Box A;Perry JM;Smith NR;Lei NY;Davies PS;Fuller MK;Haug JS;McClain M;Gracz AD;Ding S;Stelzner M;Dunn JC;Magness ST;Wong MH;Martin MG;Helmrath M;Li L
通讯作者：
Li L
影响因子：
8
作者：
Min, S-H;Kim, D. M.;Yoo, O-J
通讯作者：
Yoo, O-J
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
6.4
作者：
Preca, Bogdan-Tiberius;Bajdak, Karolina;Stemmler, Marc P.
通讯作者：
Stemmler, Marc P.
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki