The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis.
The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis.
复制标题
EGFR/miR-338-3p/EYA2 轴控制乳腺肿瘤生长和肺转移
DOI：
10.1038/cddis.2017.325
复制
发表时间：
2017-07-13
影响因子：
9
通讯作者：
Ye Q
中科院分区：
文献类型：
--
作者：
Liang Y;Xu X;Wang T;Li Y;You W;Fu J;Liu Y;Jin S;Ji Q;Zhao W;Song Q;Li L;Hong T;Huang J;Lyu Z;Ye Q
表皮生长因子受体(EGFR)的失调促进癌细胞的生长、侵袭和转移。然而，其相关的下游效应器仍然有限。在这里，我们表明，EGFR通过下调肿瘤抑制因子mioRNA-338-3p(miR-338-3p)和激活EYA2(EYA转录共激活因子和磷酸酶2)癌蛋白来促进乳腺肿瘤的生长和转移。表皮生长因子受体主要通过HIF1α转录因子抑制miR338-3p的表达。MiR-338-3p通过与EYA2的3‘-非翻译区结合来抑制EYA2的表达。EGFR通过HIF1α抑制miR-338-3p，增加EYA2的表达。通过miR-338-3p/EYA2途径，EGFR在体外和体内同种异体移植瘤小鼠模型中促进乳腺癌细胞生长、上皮向间充质转化、迁移、侵袭和肺转移。在乳腺癌患者中，miR-338-3p的表达与EGFR和EYA2的表达呈负相关，EGFR状态与EYA2的表达呈正相关，miR-338-3p和EYA2在乳腺癌中的表达预测乳腺癌肺转移。这些结果提示miR-338-3p/EYA2轴参与了EGFR介导的肿瘤生长和肺转移，针对EGFR/miR-338-3p/EYA2轴的miR-338-3p激活或EYA2抑制或联合治疗可能是治疗转移性癌症的一种有前途的方法。
Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3′-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer.
登录
查看更多内容
影响因子：
4.8
作者：
Krueger, Aaron B.;Drasin, David J.;Zhao, Rui
通讯作者：
Zhao, Rui
影响因子：
6.2
作者：
Rimawi, Mothaffar F.;Shetty, Priya B.;Weiss, Heidi L.;Schiff, Rachel;Osborne, C. Kent;Chamness, Gary C.;Elledge, Richard M.
通讯作者：
Elledge, Richard M.
影响因子：
11.2
作者：
Pore, N;Jiang, ZB;Maity, A
通讯作者：
Maity, A
影响因子：
3.8
作者：
Masuda, Hiroko;Zhang, Dongwei;Bartholomeusz, Chandra;Doihara, Hiroyoshi;Hortobagyi, Gabriel N.;Ueno, Naoto T.
通讯作者：
Ueno, Naoto T.
影响因子：
2.9
作者：
Park, Hwangseo;Ryu, Seong Eon;Kim, Seung Jun
通讯作者：
Kim, Seung Jun