ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration
ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration
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ATF4调节CCL2表达通过控制巨噬细胞浸润促进子宫内膜癌生长
DOI：
10.1016/j.yexcr.2017.08.031
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发表时间：
2017-11-15
影响因子：
3.7
通讯作者：
Gao, Yuping
中科院分区：
文献类型：
--
作者：
Liu, Bin;Chen, Pingping;Gao, Yuping
转录激活因子4（Activating transcription factor 4，ATF 4）是一种内质网应激诱导的转录因子，在肿瘤的进展和耐药中起重要作用。然而，关于其在子宫内膜癌（EC）中的作用尚无报道。在本研究中，我们发现ATF 4在EC细胞系中普遍表达。在两个EC细胞系中的功能丧失研究表明，ATF 4敲低抑制EC在体内的肿瘤生长，而不影响体外细胞增殖。来自ATF 4敲低细胞的异种移植肿瘤具有减少的M2巨噬细胞浸润。在临床标本中，与具有较低ATF 4表达的那些相比，ATF 4高表达肿瘤确实含有更多的巨噬细胞浸润。此外，我们发现，ATF 4介导的趋化因子CCL 2的表达最终导致巨噬细胞浸润和EC的肿瘤生长。综上所述，我们的研究结果表明，ATF 4通过促进CCL 2和随后的巨噬细胞募集而促进EC的肿瘤生长，并且ATF 4/CCL 2轴可能是EC的潜在治疗靶点。
Activating transcription factor 4 (ATF4), an endoplasmic reticulum stress-inducible transcription factor, plays important roles in cancer progression and resistance to therapy. However, no report is available about its roles in endometrial cancer (EC). In this study, we found that ATF4 is commonly expressed in EC cell lines. Loss-of-function studies in two EC cell lines showed that ATF4 knockdown suppresses tumor growth of EC in vivo without influencing cell proliferation in vitro. And xenograft tumors derived from ATF4-knockdown cells had reduced M2 macrophage infiltration. In clinical specimens, ATF4-high expressing tumors indeed contained more macrophage infiltration compared to those With lower ATF4 expression. Moreover, we identified that ATF4-mediated chemokine CCL2 expression ultimately results in macrophage infiltration and tumor growth of EC. Taken together, our findings suggest that ATF4 contributes to tumor growth of EC by promoting CCL2 and subsequent recruitment of macrophage, and that ATF4/CCL2 axis might be a potential therapeutic target for EC.