Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China.
Department of Oncology, 307 Hospital of People's Liberation Army, Beijing, China.
Cell Death Dis. 2017 Jul 13;8(7):e2928. doi: 10.1038/cddis.2017.325.
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.
表皮生长因子受体 (EGFR) 的失调促进了癌细胞的生长、侵袭和转移。然而，其相关的下游效应物仍然有限。在这里，我们表明 EGFR 通过下调肿瘤抑制 microRNA-338-3p（miR-338-3p）并激活 EYA2（EYA 转录共激活因子和磷酸酶 2）癌蛋白来促进乳腺癌肿瘤的生长和转移。EGFR 通过 HIF1α 转录因子大量抑制 miR-338-3p 的表达。miR-338-3p 通过结合 EYA2 的 3'-非翻译区抑制 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 通路，EGFR 增加了乳腺癌细胞在体外的生长、上皮间质转化、迁移、侵袭和肺转移，并在体内同种异体肿瘤小鼠模型中增加了肺转移。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，并且当在原发性乳腺癌中表达时，miR-338-3p 和 EYA2 预测了乳腺癌的肺转移。这些数据表明，miR-338-3p/EYA2 轴有助于 EGFR 介导的肿瘤生长和肺转移，并且激活 miR-338-3p 或抑制 EYA2 或针对 EGFR/miR-338-3p/EYA2 轴的联合治疗可能是治疗转移性癌症患者的一种有前途的方法。
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