缺氧诱导因子靶基因 MAFF 通过 IL11 和 STAT3 信号通路促进肿瘤侵袭和转移。

The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling.

机构信息

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA, USA.

MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington, UK.

出版信息

Nat Commun. 2021 Jul 14;12(1):4308. doi: 10.1038/s41467-021-24631-6.

DOI:10.1038/s41467-021-24631-6

PMID:34262028

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8280233/

Abstract

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

摘要

缺氧在肿瘤的侵袭和转移等进展过程中起着关键作用。为了确定促进侵袭和转移的受缺氧调控的关键基因，我们筛选了 50 个缺氧诱导基因，以研究它们对侵袭的影响。在这项研究中，我们发现 v-maf 肌肉腱膜纤维肉瘤癌基因同源物 F（MAFF）是一种强有力的肿瘤侵袭调控因子，而不影响细胞活力。MAFF 的表达在转移性乳腺癌患者中升高，并且与缺氧肿瘤特异性相关。结合 ChIP- 和 RNA-seq 鉴定出 IL11 是 MAFF 和 BACH1 形成的异二聚体的直接转录靶标，从而激活 STAT3 信号通路。抑制 IL11 的作用与抑制 MAFF 的作用相似，都能抑制转移。这项研究证明了 MAFF 作为 IL11/STAT3 通路在乳腺癌中的致癌作用。